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72faa803f255d880611a28f24bb6ca9500fc951f | wikidoc | INHBB | INHBB
Inhibin, beta B, also known as INHBB, is a protein which in humans is encoded by the INHBB gene. INHBB is a subunit of both activin and inhibin, two closely related glycoproteins with opposing biological effects.
# Function
## Inhibin
Inhibins are heterodimeric glycoproteins composed of an α subunit (INHA) and one of two homologous, but distinct, β subunits (βA or βB, this protein). mRNA for the two subunits has been demonstrated in the testes of adult rats. Inhibin can bind specifically to testicular interstitial cells throughout development and may be an important regulator of Leydig cell testosterone production or interstitial cell function.
The inhibin beta B subunit joins the α subunit to form a pituitary FSH secretion inhibitor. Inhibin has been shown to regulate gonadal stromal cell proliferation negatively and to have tumour-suppressor activity. In addition, serum levels of inhibin have been shown to reflect the size of granulosa-cell tumors and can therefore be used as a marker for primary as well as recurrent disease. Because expression in gonadal and various extragonadal tissues may vary severalfold in a tissue-specific fashion, it is proposed that inhibin may be both a growth/differentiation factor and a hormone.
## Activin
Furthermore, the beta B subunit forms a homodimer, activin B, and also joins with the beta A subunit to form a heterodimer, activin AB, both of which stimulate FSH secretion.
# Tissue distribution
Sections of testicular tissue from rat revealed positive immunoreactivity against anti-inhibin intensely appeared in Leydig cells. In adult animals, binding of 125I inhibin was localized primarily to the interstitial compartment of the testis. Also, Jin et al., (2001) reported that Leydig cells showed strong positive staining for the inhibin βA subunit in pigs testis.
# Receptors
In situ ligand binding studies have shown that 125I inhibin βA binds specifically to Leydig cells throughout rat testis development. These results suggest that inhibin has been considered as a regulator of Leydig cell differentiated function. Recently, additional inhibin specific binding proteins were identified in inhibin target tissues, including pituitary and Leydig cells. From these receptors β-glycan (the TGFß type III receptor) and InhBP/p120 (a membrane-tethered proteoglycan) were identified as putative inhibin receptors and they are all present in Leydig cells. However, a faint positive reaction was detected in Leydig cell cytoplasm in rats treated with anise oil. This may be related to the damaged Leydig cells, as a result of the decreasing of inhibin expression. This may be related to its content of safrole. | INHBB
Inhibin, beta B, also known as INHBB, is a protein which in humans is encoded by the INHBB gene.[1][2] INHBB is a subunit of both activin and inhibin, two closely related glycoproteins with opposing biological effects.
# Function
## Inhibin
Inhibins are heterodimeric glycoproteins composed of an α subunit (INHA) and one of two homologous, but distinct, β subunits (βA or βB, this protein). mRNA for the two subunits has been demonstrated in the testes of adult rats.[3] Inhibin can bind specifically to testicular interstitial cells throughout development and may be an important regulator of Leydig cell testosterone production or interstitial cell function.[4]
The inhibin beta B subunit joins the α subunit to form a pituitary FSH secretion inhibitor. Inhibin has been shown to regulate gonadal stromal cell proliferation negatively and to have tumour-suppressor activity. In addition, serum levels of inhibin have been shown to reflect the size of granulosa-cell tumors and can therefore be used as a marker for primary as well as recurrent disease. Because expression in gonadal and various extragonadal tissues may vary severalfold in a tissue-specific fashion, it is proposed that inhibin may be both a growth/differentiation factor and a hormone.
## Activin
Furthermore, the beta B subunit forms a homodimer, activin B, and also joins with the beta A subunit to form a heterodimer, activin AB, both of which stimulate FSH secretion.[2]
# Tissue distribution
Sections of testicular tissue from rat revealed positive immunoreactivity against anti-inhibin intensely appeared in Leydig cells.[5] In adult animals, binding of 125I inhibin was localized primarily to the interstitial compartment of the testis.[4] Also, Jin et al., (2001) reported that Leydig cells showed strong positive staining for the inhibin βA subunit in pigs testis.[6]
# Receptors
In situ ligand binding studies have shown that 125I inhibin βA binds specifically to Leydig cells throughout rat testis development. These results suggest that inhibin has been considered as a regulator of Leydig cell differentiated function.[7][8] Recently, additional inhibin specific binding proteins were identified in inhibin target tissues, including pituitary and Leydig cells.[9][10] From these receptors β-glycan (the TGFß type III receptor) and InhBP/p120 (a membrane-tethered proteoglycan) were identified as putative inhibin receptors and they are all present in Leydig cells. However, a faint positive reaction was detected in Leydig cell cytoplasm in rats treated with anise oil.[5] This may be related to the damaged Leydig cells, as a result of the decreasing of inhibin expression. This may be related to its content of safrole. | https://www.wikidoc.org/index.php/INHBB | |
30878ae55c45fb918017516317bc32989e47ff69 | wikidoc | INPP1 | INPP1
Inositol polyphosphate 1-phosphatase is an enzyme that, in humans, is encoded by the INPP1 gene.
INPP1 encodes the enzyme inositol polyphosphate-1-phosphatase, one of the enzymes involved in phosphatidylinositol signaling pathways. This enzyme removes the phosphate group at position 1 of the inositol ring from the polyphosphates inositol 1,4-bisphosphate and inositol 1,3,4-trisphophosphate.
# Model organisms
Model organisms have been used in the study of INPP1 function. A conditional knockout mouse line, called Inpp1tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice, and one significant abnormality was observed: a decreased susceptibility to bacterial infection. | INPP1
Inositol polyphosphate 1-phosphatase is an enzyme that, in humans, is encoded by the INPP1 gene.[1][2]
INPP1 encodes the enzyme inositol polyphosphate-1-phosphatase, one of the enzymes involved in phosphatidylinositol signaling pathways. This enzyme removes the phosphate group at position 1 of the inositol ring from the polyphosphates inositol 1,4-bisphosphate and inositol 1,3,4-trisphophosphate.[2]
# Model organisms
Model organisms have been used in the study of INPP1 function. A conditional knockout mouse line, called Inpp1tm1a(KOMP)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty four tests were carried out on mutant mice, and one significant abnormality was observed: a decreased susceptibility to bacterial infection.[5] | https://www.wikidoc.org/index.php/INPP1 | |
d7f2fbc9926a51b54cadeca723e1ac2af7dc126a | wikidoc | IPLEX | IPLEX
IPLEX (mecasermin rinfabate injection) is a drug developed by INSMED corporation for the treatment of growth failure in children with severe primary IGF-I deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.
Due to a patent settlement, IPLEX is being taken off the market for shortstature related indications. However, IPLEX is being studied as a treatment for other several serious medical conditions.
# Potential treatment of Myotonic Muscular Dystrophy
IPLEX is being investigated in a Phase II clinical study at the University of Rochester School of Medicine, with funding provided by the Muscular Dystrophy Association and the National Institutes of Health. This Phase II program is studying the safety and tolerability of once-daily, subcutaneous injection of IPLEX in patients with MMD. Initial data from this trial will be available in the second quarter of 2007.
# Potential treatment of HIV-Associated Adipose Redistribution Syndrome
IPLEX is also being explored as a possible therapy for HIV- Associated Adipose Redistribution Syndrome (HARS). Data is being collected from a Phase II open-label clinical study directed by Morris Schambelan, M.D., a professor of medicine at University of California San Francisco. Dr Shambelan serves as Chief of Endocrinology and Director of the General Clinical Research Center at San Francisco General Hospital. This study is designed to evaluate the safety and efficacy of IPLEX treatment with the primary goal of determining the effects of IPLEX on visceral fat distribution and glucose and lipid metabolism. Initial data from this trial is to be available in 2007, with Phase III trials initiating in 2009.
# Potential treatment of Retinopathy of Prematurity
Clinical work is at an earlier stage in the development of IPLEX to treat Retinopathy of Prematurity (ROP). This disease, affecting an estimated 14,000 to 16,000 premature infants each year, causes the lack of development of the small blood vessels in the back of the eye leading to blindness in the majority of cases. A Phase I clinical study investigating IPLEX as a treatment for ROP has been initiated at the University of Gothenburg in Sweden, in collaboration with scientists at the Harvard Medical School in the U.S. results of this study are expected by the end of 2007.
# Potential treatment of ALS
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's Disease is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Motor neurons reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. The progressive degeneration of the motor neurons in ALS eventually leads to their death. When the motor neurons die, the ability of the brain to initiate and control muscle movement is lost. With voluntary muscle action progressively affected, patients in the later stages of the disease may become totally paralyzed.
In January 2007, INSMED announced that the Italian Ministry of Health requested INSMED corporation to make IPLEX available to treat Italian patients sufferings from ALS.
# Sources
- INSMED | IPLEX
Template:Primarysources
IPLEX (mecasermin rinfabate [rDNA origin] injection) is a drug developed by INSMED corporation for the treatment of growth failure in children with severe primary IGF-I deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.
Due to a patent settlement, IPLEX is being taken off the market for shortstature related indications. However, IPLEX is being studied as a treatment for other several serious medical conditions.
# Potential treatment of Myotonic Muscular Dystrophy
IPLEX is being investigated in a Phase II clinical study at the University of Rochester School of Medicine, with funding provided by the Muscular Dystrophy Association and the National Institutes of Health. This Phase II program is studying the safety and tolerability of once-daily, subcutaneous injection of IPLEX in patients with MMD. Initial data from this trial will be available in the second quarter of 2007.
# Potential treatment of HIV-Associated Adipose Redistribution Syndrome
IPLEX is also being explored as a possible therapy for HIV- Associated Adipose Redistribution Syndrome (HARS). Data is being collected from a Phase II open-label clinical study directed by Morris Schambelan, M.D., a professor of medicine at University of California San Francisco. Dr Shambelan serves as Chief of Endocrinology and Director of the General Clinical Research Center at San Francisco General Hospital. This study is designed to evaluate the safety and efficacy of IPLEX treatment with the primary goal of determining the effects of IPLEX on visceral fat distribution and glucose and lipid metabolism. Initial data from this trial is to be available in 2007, with Phase III trials initiating in 2009.
# Potential treatment of Retinopathy of Prematurity
Clinical work is at an earlier stage in the development of IPLEX to treat Retinopathy of Prematurity (ROP). This disease, affecting an estimated 14,000 to 16,000 premature infants each year, causes the lack of development of the small blood vessels in the back of the eye leading to blindness in the majority of cases. A Phase I clinical study investigating IPLEX as a treatment for ROP has been initiated at the University of Gothenburg in Sweden, in collaboration with scientists at the Harvard Medical School in the U.S. results of this study are expected by the end of 2007.
# Potential treatment of ALS
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's Disease is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Motor neurons reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. The progressive degeneration of the motor neurons in ALS eventually leads to their death. When the motor neurons die, the ability of the brain to initiate and control muscle movement is lost. With voluntary muscle action progressively affected, patients in the later stages of the disease may become totally paralyzed.
In January 2007, INSMED announced that the Italian Ministry of Health requested INSMED corporation to make IPLEX available to treat Italian patients sufferings from ALS.
# Sources
- INSMED
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/IPLEX | |
0a42a1974a6f88b335672e4cdd56f400dbc5bec1 | wikidoc | KPNB1 | KPNB1
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Importin subunit beta-1 is a protein that in humans is encoded by the KPNB1 gene.
# Function
Nucleocytoplasmic transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. The import of proteins containing a classical nuclear localization signal (NLS) requires the NLS import receptor, a heterodimer of importin alpha and beta subunits. Each of these subunits are part of the karyopherin family of proteins. Importin alpha binds the NLS-containing cargo in the cytoplasm and importin beta docks the complex at the cytoplasmic side of the nuclear pore complex. In the presence of nucleoside triphosphates and the small GTP binding protein Ran, the complex moves into the nuclear pore complex and the importin subunits dissociate. Importin alpha enters the nucleoplasm with its passenger protein and importin beta remains at the pore. Interactions between importin beta and the FG repeats of nucleoporins are essential in translocation through the pore complex. The protein encoded by this gene is a member of the importin beta family.
# Interactions
KPNB1 has been shown to interact with:
- KPNA3,
- Karyopherin alpha 1,
- Karyopherin alpha 2,
- Mothers against decapentaplegic homolog 3,
- NUP153
- NUP50,
- NUP98,
- Nucleoporin 62,
- P53,
- Parathyroid hormone-related protein,
- RANBP1,
- RANBP2,
- Ran (biology), and
- SMN1. | KPNB1
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Importin subunit beta-1 is a protein that in humans is encoded by the KPNB1 gene.[1][2]
# Function
Nucleocytoplasmic transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. The import of proteins containing a classical nuclear localization signal (NLS) requires the NLS import receptor, a heterodimer of importin alpha and beta subunits. Each of these subunits are part of the karyopherin family of proteins. Importin alpha binds the NLS-containing cargo in the cytoplasm and importin beta docks the complex at the cytoplasmic side of the nuclear pore complex. In the presence of nucleoside triphosphates and the small GTP binding protein Ran, the complex moves into the nuclear pore complex and the importin subunits dissociate. Importin alpha enters the nucleoplasm with its passenger protein and importin beta remains at the pore. Interactions between importin beta and the FG repeats of nucleoporins are essential in translocation through the pore complex. The protein encoded by this gene is a member of the importin beta family.[3]
# Interactions
KPNB1 has been shown to interact with:
- KPNA3,[4][5]
- Karyopherin alpha 1,[4][6]
- Karyopherin alpha 2,[4][7][8]
- Mothers against decapentaplegic homolog 3,[9]
- NUP153[10][11][12]
- NUP50,[13]
- NUP98,[14][15]
- Nucleoporin 62,[6][10]
- P53,[16]
- Parathyroid hormone-related protein,[17][18]
- RANBP1,[19][20]
- RANBP2,[10][19][21]
- Ran (biology),[6][20][22] and
- SMN1.[23] | https://www.wikidoc.org/index.php/IPOB | |
f6e47431e796c6524bcbe2f18e1f7af1692b180e | wikidoc | IRAK4 | IRAK4
IRAK-4 (interleukin-1 receptor-associated kinase 4), in the IRAK family, is a protein kinase involved in signaling innate immune responses from Toll-like receptors. It also supports signaling from T-cell receptors. IRAK4 contains domain structures which are similar to those of IRAK1, IRAK2, IRAKM and Pelle. IRAK4 is unique compared to IRAK1, IRAK2 and IRAKM in that it functions upstream of the other IRAKs, but is more similar to Pelle in this trait. IRAK4 is important for its clinical applications.
Animals without IRAK-4 are more susceptible to viruses and bacteria but completely resistant to LPS challenge.
# History
The first IL-1 receptor-associated kinase (IRAK) was observed in 1994 through experiments with murine T helper cell lines D10N and EL-4. Two years later the first experimental member of this family of kinases, IRAK1, was cloned. In 2002, through database searches at the National Center for Biotechnology Information in an attempt to recognize novel members of the IRAK family, a human cDNA sequence which encoded a peptide sharing significant homology with IRAK1 was identified. This cDNA sequence was found to have five amino acid substitutions compared to IRAK1 and was termed IRAK4.
IRAK4 was proposed to be the mammalian homolog of the Pelle gene found in Drosophila melanogaster and was proposed to require its kinase activity in order for it to function in activating NF-κB. It was also proposed by Li et al. that it might function upstream of other IRAKs and possibly cause a cascade of phosphorylation events through its function as an IRAK1 kinase. This idea of a cascade of phosphorylation events was supported by a study where an IRAK4 knockout in mice showed a more severe phenotype than other IRAK knockout experiments and signalling through Toll/IL-1 receptor (TIR) is virtually eliminated.
In 2007 it was found that IRAK4 activity was necessary for activating signal pathways which lead to mitogen-activated protein kinases (MAPK), or Toll-like receptor-mediated immune responses (TLR), but was not essential to T-cell Receptor (TCR) signalling as was originally proposed.
In recent years, the role of IRAK4 in regards to melanoma and other cancers has been investigated. IRAK4 was found to be in higher levels in some lines of melanoma. By reducing the IRAK4 activity it may be possible to identify new chemotherapeutic agents to treat patients with advanced melanoma for which there is presently no effective treatment or cure.
# Protein structure
IRAK4 is a threonine/serine protein kinase made up of 460 amino acids, which contains both a kinase domain and a death domain. Its kinase domain exhibits the typical bilobal structure of kinases, with the N terminal lobe consisting of a five-stranded antiparallel beta-sheet and one alpha helix. The C terminal lobe is composed mainly of a number of alpha helices. Also contained within IRAK4’s N-terminal is an extension of twenty amino acids, which is unique to IRAK4 among kinases, even within the IRAK family. Situated where the two lobes meet is an ATP binding site, which is covered by a tyrosine gatekeeper. Tyrosine as a gatekeeper is believed to be unique to the IRAK family of kinases. The protein also contains three auto-phosphorylation sites, each of which when mutated results in a decrease in the kinase activity of IRAK4.
A structure of the autophosphorylation of the activation loop has been determined in which the activation loop Thr345 of one monomer is sitting in the active site of another monomer in the crystal (PDB: 4U9A, 4U97).
# Function, mechanism, signalling pathway
Members of interleukin-1 receptor (Il-1R) and the Toll-like receptor superfamily share an intracytoplasmic Toll-IL-1 receptor (TLR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. The TIR-IRAK signaling pathway appears to be crucial for protective immunity against specific bacteria but is redundant against most other microorganisms. IRAK4 is considered the “master IRAK” in the mammalian IRAK family because it is the only component in the IL-1/TLR signalling pathway that is absolutely crucial to its functioning. When one of these pathways is stimulated, the cell is triggered to release proinflammatory signals and to trigger innate immune actions. The loss of IRAK4, or its intrinsic kinase activity, can entirely stop signalling through these pathways.
IRAK4 is involved in signal transduction pathways stimulated by the cellular receptors belonging to the Toll/Interleukin-1 receptor superfamily. The Toll-Like Receptors (TLRs) are stimulated by recognition of pathogen-associated molecular patterns (PAMPS), whereas members of the IL-1R family are stimulated by cytokines. Both play an essential role in the immune response. The ligand binding causes conformational changes to the intracellular domain which allows for the recruitment of scaffolding proteins. One of these proteins, MyD88, uses its death domains to recruit, orient, and activate IRAK4. IRAK2 can then be phosphorylated and joins with IRAK4 and MyD88 to form the myddosome complex, which further phosphorylates and recruits IRAK1. The myddosome complex and IRAK1 recruit and activate TNF receptor-associated factor 6 (TRAF6), a ubiquitin protein ligase. TRAF6 can polyubiquitinate IKK-γ as well as itself, which recruits TGF-β activated kinase 1 (TAK1) in order to activate its ability to phosphorylate IKK-β. These pathways both work to degrade IKKγ, which releases NFκB and free it for translocation into the nucleus. Additionally, TAK1 can activate JNK to induce a MAP kinase pathway which leads to AP-1-induced gene expression. Together, AP-1 and NFκB lead to increased cytokine transcription, adhesion molecule production, and release of second messengers of infection.
Central to all of these signalling pathways is the kinase IRAK4. Results show that IRAK4 is a crucial component in an animal's response to IL-1. Animals deficient in this kinase were found to be lacking in the ability to recognize viral and bacterial invaders, and were completely resistant to lethal doses of lipopolysaccharide (LPS). This is due to IRAK4’s function as both a structural protein and as a kinase. Both of these functions are required for the myddosome complex formation. Additionally, IRAK4 has been shown to be absolutely essential in a TLR signalling. IRAK4 deficient mice have a profoundly impaired ability to produce IL-6, TNF-α, and IL-12 in response to TLR ligands. However it is worthy of note that despite its importance to many immune signalling pathways, IRAK4 does not appear to be involved in TCR signalling.
# Clinical significance
There are three components of evidence that illustrate IRAK4’s involvement in TLR signalling. First, IRAK4 is the initial kinase near the TLR receptor to activate downstream effectors such as cytokines and chemokines in the inflammatory cascade. Second, deletion of the IRAK4 gene results in various cytokine response defects and finally, patients with IRAK4 deficiency have displayed defective immunity in response to IL-1, IL-8 and other TLR binding ligands. Considering IRAK4’s downstream position of these signalling events, it is an important drug therapy target for various inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease and other autoimmune diseases.
An important area of research currently being explored is the role the IRAK4 gene may play in the development of prostate cancer. There are several interacting factors that lead to the development of this disease however genetic susceptibility of chronic inflammation has been deemed one of the most important. It has been found that mutations in the IRAK4 gene can lead to dysfunctional TLR signalling and ultimately result in increased innate immune responses and therefore an increased inflammatory response. Over time, this can lead to the onset of prostate cancer.
Another interesting application of the IRAK4 gene was found in a study involving human melanoma patients. This research found that patients with melanin-cell tumors displayed an increase in the phosphorylation state of IRAK4. The siRNA inhibition of IRAK4 in mice displayed greater programmed cell death (PCD) and slowed tumor growth. This experimental study displays yet again another avenue of IRAK4 targeting for therapeutic purposes.
A common concern with IRAK4 drug therapy or knockdown is if its absence would result in unbearable side effects considering IRAK4 plays an extremely central role in the TLR signalling pathway. Children with IRAK4 deficiency have been found to have decreased immunity to some specific bacterial infections yet not to viral, parasitic or other microbe infections. However, as these children enter adulthood and maternal antibodies are no longer present, susceptibility to infections becomes a rarity. In one study, no significant bacterial infections were documented in all investigated patients over the age of 14 with IRAK4 deficiency. This may mean that in later stages of life, IRAK4 inhibition could provide benefits against certain diseases while maintaining immunity.
The next step in this area of research is the formation of safe IRAK4 inhibitors. There has been modest progress in the development of some potential inhibitors of IRAK4 in which their mechanism works by blocking its tyrosine gated ATP binding site. All potential drugs are still currently in the early preclinical stages of development. | IRAK4
IRAK-4 (interleukin-1 receptor-associated kinase 4), in the IRAK family, is a protein kinase involved in signaling innate immune responses from Toll-like receptors. It also supports signaling from T-cell receptors. IRAK4 contains domain structures which are similar to those of IRAK1, IRAK2, IRAKM and Pelle. IRAK4 is unique compared to IRAK1, IRAK2 and IRAKM in that it functions upstream of the other IRAKs, but is more similar to Pelle in this trait. IRAK4 is important for its clinical applications.
Animals without IRAK-4 are more susceptible to viruses and bacteria but completely resistant to LPS challenge.
# History
The first IL-1 receptor-associated kinase (IRAK) was observed in 1994 through experiments with murine T helper cell lines D10N and EL-4.[1] Two years later the first experimental member of this family of kinases, IRAK1, was cloned.[2] In 2002, through database searches at the National Center for Biotechnology Information in an attempt to recognize novel members of the IRAK family, a human cDNA sequence which encoded a peptide sharing significant homology with IRAK1 was identified. This cDNA sequence was found to have five amino acid substitutions compared to IRAK1 and was termed IRAK4.[3]
IRAK4 was proposed to be the mammalian homolog of the Pelle gene found in Drosophila melanogaster and was proposed to require its kinase activity in order for it to function in activating NF-κB. It was also proposed by Li et al. that it might function upstream of other IRAKs and possibly cause a cascade of phosphorylation events through its function as an IRAK1 kinase.[3] This idea of a cascade of phosphorylation events was supported by a study where an IRAK4 knockout in mice showed a more severe phenotype than other IRAK knockout experiments and signalling through Toll/IL-1 receptor (TIR) is virtually eliminated.[3]
In 2007 it was found that IRAK4 activity was necessary for activating signal pathways which lead to mitogen-activated protein kinases (MAPK), or Toll-like receptor-mediated immune responses (TLR), but was not essential to T-cell Receptor (TCR) signalling as was originally proposed.[4]
In recent years, the role of IRAK4 in regards to melanoma and other cancers has been investigated. IRAK4 was found to be in higher levels in some lines of melanoma. By reducing the IRAK4 activity it may be possible to identify new chemotherapeutic agents to treat patients with advanced melanoma for which there is presently no effective treatment or cure.[5]
# Protein structure
IRAK4 is a threonine/serine protein kinase made up of 460 amino acids, which contains both a kinase domain and a death domain.[3] Its kinase domain exhibits the typical bilobal structure of kinases, with the N terminal lobe consisting of a five-stranded antiparallel beta-sheet and one alpha helix. The C terminal lobe is composed mainly of a number of alpha helices.[6] Also contained within IRAK4’s N-terminal is an extension of twenty amino acids, which is unique to IRAK4 among kinases, even within the IRAK family.[7] Situated where the two lobes meet is an ATP binding site, which is covered by a tyrosine gatekeeper. Tyrosine as a gatekeeper is believed to be unique to the IRAK family of kinases.[6] The protein also contains three auto-phosphorylation sites, each of which when mutated results in a decrease in the kinase activity of IRAK4.[8]
A structure of the autophosphorylation of the activation loop has been determined in which the activation loop Thr345 of one monomer is sitting in the active site of another monomer in the crystal (PDB: 4U9A, 4U97).[9][10]
# Function, mechanism, signalling pathway
Members of interleukin-1 receptor (Il-1R) and the Toll-like receptor superfamily share an intracytoplasmic Toll-IL-1 receptor (TLR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. The TIR-IRAK signaling pathway appears to be crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.[11] IRAK4 is considered the “master IRAK” in the mammalian IRAK family because it is the only component in the IL-1/TLR signalling pathway that is absolutely crucial to its functioning. When one of these pathways is stimulated, the cell is triggered to release proinflammatory signals and to trigger innate immune actions. The loss of IRAK4, or its intrinsic kinase activity, can entirely stop signalling through these pathways.[12]
IRAK4 is involved in signal transduction pathways stimulated by the cellular receptors belonging to the Toll/Interleukin-1 receptor superfamily. The Toll-Like Receptors (TLRs) are stimulated by recognition of pathogen-associated molecular patterns (PAMPS), whereas members of the IL-1R family are stimulated by cytokines.[13] Both play an essential role in the immune response. The ligand binding causes conformational changes to the intracellular domain which allows for the recruitment of scaffolding proteins. One of these proteins, MyD88, uses its death domains to recruit, orient, and activate IRAK4. IRAK2 can then be phosphorylated and joins with IRAK4 and MyD88 to form the myddosome complex, which further phosphorylates and recruits IRAK1.[14] The myddosome complex and IRAK1 recruit and activate TNF receptor-associated factor 6 (TRAF6), a ubiquitin protein ligase.[3] TRAF6 can polyubiquitinate IKK-γ as well as itself, which recruits TGF-β activated kinase 1 (TAK1) in order to activate its ability to phosphorylate IKK-β. These pathways both work to degrade IKKγ, which releases NFκB and free it for translocation into the nucleus. Additionally, TAK1 can activate JNK to induce a MAP kinase pathway which leads to AP-1-induced gene expression.[4] Together, AP-1 and NFκB lead to increased cytokine transcription, adhesion molecule production, and release of second messengers of infection.[14]
Central to all of these signalling pathways is the kinase IRAK4. Results show that IRAK4 is a crucial component in an animal's response to IL-1. Animals deficient in this kinase were found to be lacking in the ability to recognize viral and bacterial invaders, and were completely resistant to lethal doses of lipopolysaccharide (LPS).[13] This is due to IRAK4’s function as both a structural protein and as a kinase. Both of these functions are required for the myddosome complex formation. Additionally, IRAK4 has been shown to be absolutely essential in a TLR signalling. IRAK4 deficient mice have a profoundly impaired ability to produce IL-6, TNF-α, and IL-12 in response to TLR ligands. However it is worthy of note that despite its importance to many immune signalling pathways, IRAK4 does not appear to be involved in TCR signalling.[4]
# Clinical significance
There are three components of evidence that illustrate IRAK4’s involvement in TLR signalling. First, IRAK4 is the initial kinase near the TLR receptor to activate downstream effectors such as cytokines and chemokines in the inflammatory cascade.[3] Second, deletion of the IRAK4 gene results in various cytokine response defects and finally, patients with IRAK4 deficiency have displayed defective immunity in response to IL-1, IL-8 and other TLR binding ligands.[13] Considering IRAK4’s downstream position of these signalling events, it is an important drug therapy target for various inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease and other autoimmune diseases.[14]
An important area of research currently being explored is the role the IRAK4 gene may play in the development of prostate cancer. There are several interacting factors that lead to the development of this disease however genetic susceptibility of chronic inflammation has been deemed one of the most important. It has been found that mutations in the IRAK4 gene can lead to dysfunctional TLR signalling and ultimately result in increased innate immune responses and therefore an increased inflammatory response. Over time, this can lead to the onset of prostate cancer.[15]
Another interesting application of the IRAK4 gene was found in a study involving human melanoma patients. This research found that patients with melanin-cell tumors displayed an increase in the phosphorylation state of IRAK4. The siRNA inhibition of IRAK4 in mice displayed greater programmed cell death (PCD) and slowed tumor growth.[14] This experimental study displays yet again another avenue of IRAK4 targeting for therapeutic purposes.
A common concern with IRAK4 drug therapy or knockdown is if its absence would result in unbearable side effects considering IRAK4 plays an extremely central role in the TLR signalling pathway.[12] Children with IRAK4 deficiency have been found to have decreased immunity to some specific bacterial infections yet not to viral, parasitic or other microbe infections. However, as these children enter adulthood and maternal antibodies are no longer present, susceptibility to infections becomes a rarity. In one study, no significant bacterial infections were documented in all investigated patients over the age of 14 with IRAK4 deficiency. This may mean that in later stages of life, IRAK4 inhibition could provide benefits against certain diseases while maintaining immunity.[16]
The next step in this area of research is the formation of safe IRAK4 inhibitors. There has been modest progress in the development of some potential inhibitors of IRAK4 in which their mechanism works by blocking its tyrosine gated ATP binding site. All potential drugs are still currently in the early preclinical stages of development.[17] | https://www.wikidoc.org/index.php/IRAK4 | |
1590574eabe9b5c9ca136166ed25643dfddad5db | wikidoc | ISFET | ISFET
# Overview
An ISFET is an ion-sensitive field effect transistor used to measure ion concentrations in solution; when the ion concentration (such as pH) changes, the current through the transistor will change accordingly. Here, the solution is used as the gate electrode. A voltage between substrate and oxide surfaces arises due to an ions sheath.
The surface hydrolyzation of OH groups of the gate materials varies in aqueous solutions due to pH value. Typical gate materials are Si3N4, Al2O3 and Ta2O5.
An ISFET's source and drain are constructed as for a MOSFET. The gate electrode is separated from the channel by a barrier which is sensitive to hydrogen ions and a gap to allow the substance under test to come in contact with the sensitive barrier. An ISFET's threshold voltage depends on the pH of the substance in contact with its ion-sensitive barrier. | ISFET
# Overview
An ISFET is an ion-sensitive field effect transistor used to measure ion concentrations in solution; when the ion concentration (such as pH) changes, the current through the transistor will change accordingly. Here, the solution is used as the gate electrode. A voltage between substrate and oxide surfaces arises due to an ions sheath.
The surface hydrolyzation of OH groups of the gate materials varies in aqueous solutions due to pH value. Typical gate materials are Si3N4, Al2O3 and Ta2O5.
An ISFET's source and drain are constructed as for a MOSFET. The gate electrode is separated from the channel by a barrier which is sensitive to hydrogen ions and a gap to allow the substance under test to come in contact with the sensitive barrier. An ISFET's threshold voltage depends on the pH of the substance in contact with its ion-sensitive barrier. | https://www.wikidoc.org/index.php/ISFET | |
53d2716258999ba07c3178c237eae98f8b28bf83 | wikidoc | ISG15 | ISG15
Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ISG15 gene. The main cellular function of the protein is ISGylation, its covalent addition to cytoplasmic and nuclear proteins, similar to ubiquitination. In addition, ISG15 has anti-viral activity.
ISG15 shares several common properties with other ubiquitin-like proteins (UBLs), but its activity is tightly regulated by specific signaling pathways that have a role in innate immunity. ISG15 was identified as an interferon stimulated gene (ISG) since its expression is induced in response to type I interferons or lipopolysaccharide treatment. Upon interferon treatment, ISG15 can be detected in both free and conjugated forms, and is secreted from monocytes and lymphocytes where it can function as a cytokine. In the cell, ISG15 co-localizes with intermediate filaments and ISGylation may modulate the JAK-STAT pathway or certain aspects of neurological disease. It is also known as UCRP (ubiquitin cross-reactive protein) since it contains 2 tandem ubiquitin homology domains and is cross-reactive with ubiquitin antibodies. In contrast to other UBLs, ISG15 has not been identified in lower eukaryotes (yeast, nematode, insects, plants) indicating its role in specialized functions.
# ISGylation
The mechanism of ISGylation and deISGylation is similar to that of ubiquitin, although the complete system components have not yet been identified. The activating E1 enzyme (UBE1L) charges ISG15 by forming a high-energy thiolester intermediate and transfers it to the UbcH8 E2 protein. UbcH8 has been identified as the major E2 for ISGylation, although it also functions in ubiquitination. The E2 protein subsequently transfers the ISG15 to specific E3 ligases (Herc5) and relevant intracellular substrates. Only one deconjugating protease with specificity to ISG15 has been identified to date: UBP43 (a member of the USP family) cleaves ISG15-peptide fusions and also removes ISG15 (deISGylation) from native conjugates.
# Pathology
In pancreatic ductal adenocarcinoma, tumor-associated macrophages secrete ISG15 enhancing the phenotype of cancer stem cells in the tumor. | ISG15
Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ISG15 gene.[1][2] The main cellular function of the protein is ISGylation, its covalent addition to cytoplasmic and nuclear proteins, similar to ubiquitination. In addition, ISG15 has anti-viral activity.[3]
ISG15 shares several common properties with other ubiquitin-like proteins (UBLs), but its activity is tightly regulated by specific signaling pathways that have a role in innate immunity. ISG15 was identified as an interferon stimulated gene (ISG) since its expression is induced in response to type I interferons or lipopolysaccharide treatment. Upon interferon treatment, ISG15 can be detected in both free and conjugated forms, and is secreted from monocytes and lymphocytes where it can function as a cytokine. In the cell, ISG15 co-localizes with intermediate filaments and ISGylation may modulate the JAK-STAT pathway or certain aspects of neurological disease. It is also known as UCRP (ubiquitin cross-reactive protein) since it contains 2 tandem ubiquitin homology domains and is cross-reactive with ubiquitin antibodies. In contrast to other UBLs, ISG15 has not been identified in lower eukaryotes (yeast, nematode, insects, plants) indicating its role in specialized functions.
# ISGylation
The mechanism of ISGylation and deISGylation is similar to that of ubiquitin, although the complete system components have not yet been identified. The activating E1 enzyme (UBE1L) charges ISG15 by forming a high-energy thiolester intermediate and transfers it to the UbcH8 E2 protein. UbcH8 has been identified as the major E2 for ISGylation, although it also functions in ubiquitination. The E2 protein subsequently transfers the ISG15 to specific E3 ligases (Herc5[4]) and relevant intracellular substrates. Only one deconjugating protease with specificity to ISG15 has been identified to date: UBP43 (a member of the USP family) cleaves ISG15-peptide fusions and also removes ISG15 (deISGylation) from native conjugates.[5]
# Pathology
In pancreatic ductal adenocarcinoma, tumor-associated macrophages secrete ISG15 enhancing the phenotype of cancer stem cells in the tumor.[6] | https://www.wikidoc.org/index.php/ISG15 | |
83ace7f8caa5bd9790a18788ed99599e56e38fef | wikidoc | iSOFT | iSOFT
iSOFT is an international supplier of software applications for the healthcare sector. Its products are used by more than 8,000 organisations in 27 countries for managing patient information and healthcare services.
The company, which has its headquarters in England, is heavily involved in the UK National Health Service's National Programme for IT (NPfIT), which aims to connect over 30,000 doctors in general practice to almost 300 hospitals and to give patients access to their own healthcare information.
Although iSOFT’s revenue increased by 8.4% to just over £200m in 2005-6, the company reported a pre-tax loss of £343.8m for the 12 months ended 30 April 2006, due mainly to a one-off ‘goodwill impairment’ charge of £351.4m – a non-cash adjustment related to iSOFT’s acquisition of other companies in recent years.
In August 2006, it was confirmed that the UK government watchdog, the Financial Services Authority (FSA), was investigating possible accounting irregularities at iSOFT, in relation to the years ended 30 April 2004 and 2005.
On 23rd January 2007, the sale of iSOFT started to move forward, with three companies being shortlisted as bidders for the company. The Times newspaper listed U.S. healthcare IT providers Cerner and McKesson, as well as U.S. private equity company General Atlantic as the three companies looking at a package of around £200m to purchase iSoft.
On 16th May 2007, iSOFT announced its recommendation to accept a merger with Australian company IBA Health in an all-stock deal.
On 6th June 2007, Computer_Sciences_Corporation said it was not excluding the possibility of a CSC bid for iSOFT.
On 6th July 2007, iSOFT shareholders voted in favour of the IBA Health offer.
On 20th July 2007, CompuGROUP made an eleventh hour offer. iSOFT directors considered this proposal and concluded that the offer represented better value to iSOFT shareholders than the IBA offer. More details here.
On 21st August 2007, IBA made a revised offer and the iSOFT board recommended acceptance by shareholders. CompuGROUP said in response that it would not be increasing its own offer. | iSOFT
Template:Infobox Company
iSOFT is an international supplier of software applications for the healthcare sector. Its products are used by more than 8,000 organisations in 27 countries for managing patient information and healthcare services.
The company, which has its headquarters in England, is heavily involved in the UK National Health Service's National Programme for IT (NPfIT), which aims to connect over 30,000 doctors in general practice to almost 300 hospitals and to give patients access to their own healthcare information.
Although iSOFT’s revenue increased by 8.4% to just over £200m in 2005-6, the company reported a pre-tax loss of £343.8m for the 12 months ended 30 April 2006, due mainly to a one-off ‘goodwill impairment’ charge of £351.4m – a non-cash adjustment related to iSOFT’s acquisition of other companies in recent years.
In August 2006, it was confirmed that the UK government watchdog, the Financial Services Authority (FSA), was investigating possible accounting irregularities at iSOFT, in relation to the years ended 30 April 2004 and 2005.
On 23rd January 2007, the sale of iSOFT started to move forward, with three companies being shortlisted as bidders for the company. The Times newspaper listed U.S. healthcare IT providers Cerner and McKesson, as well as U.S. private equity company General Atlantic as the three companies looking at a package of around £200m to purchase iSoft.
On 16th May 2007, iSOFT announced its recommendation to accept a merger with Australian company IBA Health in an all-stock deal. [1]
On 6th June 2007, Computer_Sciences_Corporation said it was not excluding the possibility of a CSC bid for iSOFT.
On 6th July 2007, iSOFT shareholders voted in favour of the IBA Health offer.
On 20th July 2007, CompuGROUP made an eleventh hour offer. iSOFT directors considered this proposal and concluded that the offer represented better value to iSOFT shareholders than the IBA offer. More details here.
On 21st August 2007, IBA made a revised offer and the iSOFT board recommended acceptance by shareholders. CompuGROUP said in response that it would not be increasing its own offer. | https://www.wikidoc.org/index.php/ISOFT | |
cbf1be2e7ad80c23f5b71917d0030dfd2c56ddcf | wikidoc | ITFG3 | ITFG3
Protein ITFG3 also known as family with sequence similarity 234 member A (FAM234A) is a protein that in humans is encoded by the ITFG3 gene. Here, the gene is explored as encoded by mRNA found in Homo sapiens. The FAM234A gene is conserved in mice, rats, chickens, zebrafish, dogs, cows, frogs, chimpanzees, and rhesus monkeys. Orthologs of the gene can be found in at least 220 organisms including the tropical clawed frog, pandas, and Chinese hamsters. The gene is located at 16p13.3 and has a total of 19 exons. The mRNA has a total of 3224 bp and the protein has 552 aa. The molecular mass of the protein produced by this gene is 59660 Da. It is expressed in at least 27 tissue types in humans, with the greatest presence in the duodenum, fat, small intestine, and heart.
A “Newfoundland deletion” or a0-thalassemia deletion has been found within the second intervening sequence of the FAM234A gene. The gene is associated with multiple red blood cell phenotypes in African Americans – though the exact function or effect of the gene was not entirely clear. Review of GeneCards’ current database on the FAM234A gene provided no additional elucidation on the function of the gene.
# Gene
FAM234A is located on Chromosome 16 (234,546 - 269, 943). It is 35,398 bases long, contains 11 exons, and is oriented on the plus strand in the 5' to 3' direction. Other aliases include ITFG3, C16orf9, and gs19.
There are no known paralogs of FAM234A.
The FAM234A gene is conserved in at least 220 organisms, with no evidence for conservation of the gene in single celled organisms. Listed below is a selection of orthologs with the estimated date of divergence from human lineage in million years ago (MYA), the accession number, and the % identity to human FAM234A. This list does not contain all of the known orthologs.
# mRNA
There are at least 11 FAM234A isoforms. Aside from the longest transcript, the other isoforms differ by truncation, primarily at the 3' end. This results in a wide variation in sequence length between isoforms.
# Protein
The FAM234A gene encodes a serine and leucine rich protein titled the "FAM234A Protein" or ITFG3. The encoded protein is 552 amino acids in length with a predicted molecular weight of 59,660Da and a basal isoelectric point of 5.84. The FAM234A protein has a notable hydrophobic region from position 49-70 in the amino acid sequence that correlates with one of the two trans-membrane regions found on FAM234A. FAM234A has membrane topology type 3a, indicating multiple trans-membrane regions with it's N-terminus facing the cytosol. The protein is predicted to be located in the endoplasmic reticulum, with portions of it found within the endoplasmic reticulum lumen. Within the cell, FAM234A has also been localized to the ribosomes and nucleus. | ITFG3
Protein ITFG3 also known as family with sequence similarity 234 member A (FAM234A) is a protein that in humans is encoded by the ITFG3 gene.[1][2] Here, the gene is explored as encoded by mRNA found in Homo sapiens. The FAM234A gene is conserved in mice, rats, chickens, zebrafish, dogs, cows, frogs, chimpanzees, and rhesus monkeys.[3] Orthologs of the gene can be found in at least 220 organisms including the tropical clawed frog, pandas, and Chinese hamsters.[4] The gene is located at 16p13.3 and has a total of 19 exons. The mRNA has a total of 3224 bp and the protein has 552 aa.[5][3] The molecular mass of the protein produced by this gene is 59660 Da.[6] It is expressed in at least 27 tissue types in humans, with the greatest presence in the duodenum, fat, small intestine, and heart.[3]
A “Newfoundland deletion” or a0-thalassemia deletion has been found within the second intervening sequence of the FAM234A gene.[7] The gene is associated with multiple red blood cell phenotypes in African Americans – though the exact function or effect of the gene was not entirely clear.[8] Review of GeneCards’ current database on the FAM234A gene provided no additional elucidation on the function of the gene.[6]
# Gene
FAM234A is located on Chromosome 16 (234,546 - 269, 943). It is 35,398 bases long, contains 11 exons, and is oriented on the plus strand in the 5' to 3' direction. Other aliases include ITFG3, C16orf9, and gs19.
There are no known paralogs of FAM234A.
The FAM234A gene is conserved in at least 220 organisms, with no evidence for conservation of the gene in single celled organisms. Listed below is a selection of orthologs with the estimated date of divergence from human lineage in million years ago (MYA), the accession number, and the % identity to human FAM234A. This list does not contain all of the known orthologs.
# mRNA
There are at least 11 FAM234A isoforms. Aside from the longest transcript, the other isoforms differ by truncation, primarily at the 3' end. This results in a wide variation in sequence length between isoforms.
# Protein
The FAM234A gene encodes a serine and leucine rich protein titled the "FAM234A Protein" or ITFG3. The encoded protein is 552 amino acids in length with a predicted molecular weight of 59,660Da and a basal isoelectric point of 5.84.[9] The FAM234A protein has a notable hydrophobic region from position 49-70 in the amino acid sequence that correlates with one of the two trans-membrane regions found on FAM234A.[10] FAM234A has membrane topology type 3a, indicating multiple trans-membrane regions with it's N-terminus facing the cytosol. The protein is predicted to be located in the endoplasmic reticulum, with portions of it found within the endoplasmic reticulum lumen.[10] Within the cell, FAM234A has also been localized to the ribosomes and nucleus.[11] | https://www.wikidoc.org/index.php/ITFG3 | |
723e44cbeeefd9aa811973f70e6890996b3aa610 | wikidoc | ITGA7 | ITGA7
Alpha-7 integrin is a protein that in humans is encoded by the ITGA7 gene. Alpha-7 integrin is critical for modulating cell-matrix interactions. Alpha-7 integrin is highly expressed in cardiac muscle, skeletal muscle and smooth muscle cells, and localizes to Z-disc and costamere structures. Mutations in ITGA7 have been associated with congenital myopathies and noncompaction cardiomyopathy, and altered expression levels of alpha-7 integrin have been identified in various forms of muscular dystrophy.
# Structure
ITGA7 encodes the protein alpha-7 integrin. Alpha-7 integrin is 128.9 kDa in molecular weight and 1181 amino acids in length. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alpha-7 integrin undergoes post-translational cleavage within the extracellular domain to yield disulfide-linked light and heavy chains that join with beta 1 to form an integrin that binds to the extracellular matrix protein laminin-1. The primary binding partners of alpha-7 integrin are laminin-1 (alpha1-beta1-gamma1), laminin-2 (alpha2-beta1-gamma1) and laminin-4 (alpha2-beta2-gamma1). Alpha-7/beta-1 is the major integrin complex expressed in differentiated muscle cells.
Splice variants of alpha-7 integrin that differ in both the extracellular and cytoplasmic domains exist in the mouse and are developmentally regulated in mouse and rat muscle tissue. The X1/X2 alternative splicing region lies in the extracellular domain and alters the ligand binding site; specifically, the conserved homology repeat domains 3 and 4. The first identified human transcript contains extracellular and cytoplasmic domains corresponding to the mouse X2 and B variants, respectively. A unique extracellular splice variant was also identified in human. The differentially spliced variants detected in rodents have also been detected in humans. Major cytoplasmic, developmentally regulated variants, alpha-7A and alpha-7B, as well as extracellular variants, X1 and X2 were identified in humans. Moreover, the D variant, but not the C variant was detected in humans.
Alpha-7 integrin is highly expressed in striated muscle, namely skeletal and cardiac muscle, and functions as the major laminin-binding integrin. It was later shown that alpha-7 integrin is also highly expressed in smooth muscle. The two major splice variants of alpha-7 integrin appear to have developmentally regulated expression; alpha-7A integrin is expressed solely in skeletal muscle, however alpha-7B integrin is expressed more loosely in striated muscle as well as the vasculature.
# Function
The function of alpha-7 integrin, as is the case for most integrins is to mediate cell membrane interactions with extracellular matrix.
The alpha-7/beta-1 integrin complex clearly plays a role in the development of striated muscle and smooth muscle. Alpha-7/beta-1 integrin promotes the adhesion and motility of myoblasts, and is likely important in the recruitment of myogenic precursors during muscle differentiation. It was shown however that beta-1D integrin appears at embryonic day 11 and alpha-7 integrin does not appear until embryonic day 17; thus, beta-1D associates with alternate alpha subunits (alpha-5, alpha-6A) prior to alpha-7. In human skeletal muscle, alpha-7 integrin is also developmentally regulated, being first detected at age 2.
In adult striated muscle cells, alpha-7 integrin (complexed to beta-1 integrin) is localized to Z-discs and costamere structures, bound to the four and one half LIM domain proteins, FHL1 and FHL2. It has been demonstrated that alpha-7 integrin can be mono-ADP-ribosylated on the cell surface in skeletal muscle cells; however, the functional significance of this modification has not been investigated.
Insights into the function of alpha-7 integrin have come from studies employing mouse transgenesis. A mouse expressing a null allele of the ITGA7 gene are viable, suggesting that alpha-7 integrin is not essential for normal myogenesis; however, these mice develop a phenotype that resembles muscular dystrophy. In soleus muscle, there was a significant disruption of myotendinous junctions, variation in the size of fibers, centrally located nuclei, necrosis, phagocytosis, and elevated serum levels of creatine kinase. It has also been proposed that alpha-7 integrin and gamma-sarcoglycan have overlapping functions in skeletal muscle. In support of this, a double knockout of gamma-sarcoglycan and alpha-7 integrin produced a phenotype that was far worse than either knockout alone. Mice died within 1 month of birth and had severe muscle degeneration, suggesting that the roles of these proteins may overlap to maintain the stability of the sarcolemma. Moreover, the double knockout of dystrophin and alpha-7 integrin produced a Duchenne muscular dystrophy-like phenotype, and demonstrated that alterations in alpha-7 integrin affect the pathological changes observed in dystrophin deficiencies. In support of this notion, AAV overexpression of ITGA7 in skeletal muscle of Duchenne muscular dystrophy (DMD) mice showed a significant protective effect against adverse functional parameters associated with DMD, combined with a reversal of these negative features, suggesting that alpha-7 integrin may be a potential therapeutic candidate to treat Duchenne muscular dystrophy.
Studies employing mutant alpha-7 integrin constructs have shown that the cytoplasmic tail of alpha-7B integrin is essential for regulation of lamellipodia formation and regulation of cell mobility regulation via laminin-1/E8 and p130(CAS)/Crk complex formation.
# Clinical Significance
Mutations in ITGA7 have been found in patients with unclassified congenital myopathy. Additionally, in patients with severe congenital fiber type disproportion and left ventricular non-compaction cardiomyopathy, a missense mutation, Glu882Lys, was identified in ITGA7 along with a missense mutation in MYH7B, both novel disease genes having a synergistic effect on disease severity.
Alpha-7B integrin expression has been shown to be significantly decreased at sarcolemmal membranes in patients with laminin alpha2 chain-deficient congenital muscular dystrophy. Additionally, in Duchenne muscular dystrophy and Becker muscular dystrophy, the expression of alpha-7B integrin was enhanced.
# Interactions
ITGA7 has been shown to interact with:
- Merosin
- ITGB1
- FHL2 and
- FHL3. | ITGA7
Alpha-7 integrin is a protein that in humans is encoded by the ITGA7 gene.[1][2] Alpha-7 integrin is critical for modulating cell-matrix interactions. Alpha-7 integrin is highly expressed in cardiac muscle, skeletal muscle and smooth muscle cells, and localizes to Z-disc and costamere structures. Mutations in ITGA7 have been associated with congenital myopathies and noncompaction cardiomyopathy, and altered expression levels of alpha-7 integrin have been identified in various forms of muscular dystrophy.
# Structure
ITGA7 encodes the protein alpha-7 integrin. Alpha-7 integrin is 128.9 kDa in molecular weight and 1181 amino acids in length.[3] Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alpha-7 integrin undergoes post-translational cleavage within the extracellular domain to yield disulfide-linked light and heavy chains that join with beta 1 to form an integrin that binds to the extracellular matrix protein laminin-1. The primary binding partners of alpha-7 integrin are laminin-1 (alpha1-beta1-gamma1), laminin-2 (alpha2-beta1-gamma1) and laminin-4 (alpha2-beta2-gamma1).[4] Alpha-7/beta-1 is the major integrin complex expressed in differentiated muscle cells.
Splice variants of alpha-7 integrin that differ in both the extracellular and cytoplasmic domains exist in the mouse[5] and are developmentally regulated in mouse and rat muscle tissue.[5][6][7][8][9] The X1/X2 alternative splicing region lies in the extracellular domain and alters the ligand binding site; specifically, the conserved homology repeat domains 3 and 4.[5] The first identified human transcript contains extracellular and cytoplasmic domains corresponding to the mouse X2 and B variants, respectively. A unique extracellular splice variant was also identified in human.[2][10] The differentially spliced variants detected in rodents have also been detected in humans. Major cytoplasmic, developmentally regulated variants, alpha-7A and alpha-7B, as well as extracellular variants, X1 and X2 were identified in humans. Moreover, the D variant, but not the C variant was detected in humans.[11]
Alpha-7 integrin is highly expressed in striated muscle, namely skeletal and cardiac muscle, and functions as the major laminin-binding integrin.[12] It was later shown that alpha-7 integrin is also highly expressed in smooth muscle.[13] The two major splice variants of alpha-7 integrin appear to have developmentally regulated expression; alpha-7A integrin is expressed solely in skeletal muscle, however alpha-7B integrin is expressed more loosely in striated muscle as well as the vasculature.[14]
# Function
The function of alpha-7 integrin, as is the case for most integrins is to mediate cell membrane interactions with extracellular matrix.[15]
The alpha-7/beta-1 integrin complex clearly plays a role in the development of striated muscle and smooth muscle. Alpha-7/beta-1 integrin promotes the adhesion and motility of myoblasts, and is likely important in the recruitment of myogenic precursors during muscle differentiation.[16] It was shown however that beta-1D integrin appears at embryonic day 11 and alpha-7 integrin does not appear until embryonic day 17; thus, beta-1D associates with alternate alpha subunits (alpha-5, alpha-6A) prior to alpha-7.[17] In human skeletal muscle, alpha-7 integrin is also developmentally regulated, being first detected at age 2.[4]
In adult striated muscle cells, alpha-7 integrin (complexed to beta-1 integrin) is localized to Z-discs and costamere structures, bound to the four and one half LIM domain proteins, FHL1 and FHL2.[6][18][19] It has been demonstrated that alpha-7 integrin can be mono-ADP-ribosylated on the cell surface in skeletal muscle cells;[20] however, the functional significance of this modification has not been investigated.
Insights into the function of alpha-7 integrin have come from studies employing mouse transgenesis. A mouse expressing a null allele of the ITGA7 gene are viable, suggesting that alpha-7 integrin is not essential for normal myogenesis; however, these mice develop a phenotype that resembles muscular dystrophy. In soleus muscle, there was a significant disruption of myotendinous junctions, variation in the size of fibers, centrally located nuclei, necrosis, phagocytosis, and elevated serum levels of creatine kinase.[21] It has also been proposed that alpha-7 integrin and gamma-sarcoglycan have overlapping functions in skeletal muscle. In support of this, a double knockout of gamma-sarcoglycan and alpha-7 integrin produced a phenotype that was far worse than either knockout alone. Mice died within 1 month of birth and had severe muscle degeneration, suggesting that the roles of these proteins may overlap to maintain the stability of the sarcolemma.[22] Moreover, the double knockout of dystrophin and alpha-7 integrin produced a Duchenne muscular dystrophy-like phenotype, and demonstrated that alterations in alpha-7 integrin affect the pathological changes observed in dystrophin deficiencies.[23] In support of this notion, AAV overexpression of ITGA7 in skeletal muscle of Duchenne muscular dystrophy (DMD) mice showed a significant protective effect against adverse functional parameters associated with DMD, combined with a reversal of these negative features, suggesting that alpha-7 integrin may be a potential therapeutic candidate to treat Duchenne muscular dystrophy.[24]
Studies employing mutant alpha-7 integrin constructs have shown that the cytoplasmic tail of alpha-7B integrin is essential for regulation of lamellipodia formation and regulation of cell mobility regulation via laminin-1/E8 and p130(CAS)/Crk complex formation.[25]
# Clinical Significance
Mutations in ITGA7 have been found in patients with unclassified congenital myopathy.[26] Additionally, in patients with severe congenital fiber type disproportion and left ventricular non-compaction cardiomyopathy, a missense mutation, Glu882Lys, was identified in ITGA7 along with a missense mutation in MYH7B, both novel disease genes having a synergistic effect on disease severity.[27]
Alpha-7B integrin expression has been shown to be significantly decreased at sarcolemmal membranes in patients with laminin alpha2 chain-deficient congenital muscular dystrophy. Additionally, in Duchenne muscular dystrophy and Becker muscular dystrophy, the expression of alpha-7B integrin was enhanced.[4]
# Interactions
ITGA7 has been shown to interact with:
- Merosin[28]
- ITGB1[29][30]
- FHL2[31] and
- FHL3.[31] | https://www.wikidoc.org/index.php/ITGA7 | |
2f153062a73da7ddcc280f2882ef9b53f35cadb3 | wikidoc | ITGA9 | ITGA9
Integrin alpha-9 is a protein that in humans is encoded by the ITGA9 gene.
# Function
This gene encodes an alpha integrin. Integrins are heterodimeric integral membrane glycoproteins composed of an alpha chain and a beta chain that mediate cell-cell and cell-matrix adhesion. The protein encoded by this gene, when bound to the beta 1 chain, forms an integrin that is a receptor for tenascin-C, VCAM1 and osteopontin. Expression of this gene has been found to be upregulated in small cell lung cancers.
# Interactions
The α9 subunit forms a heterodimeric complex with a β1 subunit to form the α9β1 integrin. This integrin participates in cell adhesion with various ligands in the extracellular matrix (ECM), including extra domain A (EDA) fibronectin, tenascin-C, ADAMs, EMELIN1, osteopontin, and VEGF. α9β1 binding is independent of the RGD peptide sequence. | ITGA9
Integrin alpha-9 is a protein that in humans is encoded by the ITGA9 gene.[1][2][3]
# Function
This gene encodes an alpha integrin. Integrins are heterodimeric integral membrane glycoproteins composed of an alpha chain and a beta chain that mediate cell-cell and cell-matrix adhesion. The protein encoded by this gene, when bound to the beta 1 chain, forms an integrin that is a receptor for tenascin-C, VCAM1 and osteopontin. Expression of this gene has been found to be upregulated in small cell lung cancers.[3]
# Interactions
The α9 subunit forms a heterodimeric complex with a β1 subunit to form the α9β1 integrin. This integrin participates in cell adhesion with various ligands in the extracellular matrix (ECM), including extra domain A (EDA) fibronectin, tenascin-C, ADAMs, EMELIN1, osteopontin, and VEGF.[4] α9β1 binding is independent of the RGD peptide sequence. | https://www.wikidoc.org/index.php/ITGA9 | |
83cd43d78757e4c080f4ecce5cc46bb34a1d9cfb | wikidoc | ITGAV | ITGAV
Integrin alpha-V is a protein that in humans is encoded by the ITGAV gene.
# Function
ITGAV encodes integrin alpha chain V. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alpha V undergoes post-translational cleavage to yield disulfide-linked heavy and light chains, that combine with multiple integrin beta chains to form different integrins. Among the known associating beta chains (beta chains 1,3,5,6, and 8; 'ITGB1', 'ITGB3', 'ITGB5', 'ITGB6', and 'ITGB8'), each can interact with extracellular matrix ligands; the alpha V beta 3 integrin, perhaps the most studied of these, is referred to as the Vitronectin receptor (VNR). In addition to adhesion, many integrins are known to facilitate signal transduction.
# Alpha V class integrins
In mammals the integrins that include alpha-V are :
# Clinical significance
Overexpression of the ITGAV gene is associated with progression and spread of colorectal cancer, and prostate cancer.
# As a drug target
The mAbs intetumumab, and abituzumab target this protein which is found on some tumour cells. | ITGAV
Integrin alpha-V is a protein that in humans is encoded by the ITGAV gene.[1]
# Function
ITGAV encodes integrin alpha chain V. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. Alpha V undergoes post-translational cleavage to yield disulfide-linked heavy and light chains, that combine with multiple integrin beta chains to form different integrins. Among the known associating beta chains (beta chains 1,3,5,6, and 8; 'ITGB1', 'ITGB3', 'ITGB5', 'ITGB6', and 'ITGB8'), each can interact with extracellular matrix ligands; the alpha V beta 3 integrin, perhaps the most studied of these, is referred to as the Vitronectin receptor (VNR). In addition to adhesion, many integrins are known to facilitate signal transduction.[2]
# Alpha V class integrins
In mammals the integrins that include alpha-V are :
# Clinical significance
Overexpression of the ITGAV gene is associated with progression and spread of colorectal cancer,[4] and prostate cancer.[5]
# As a drug target
The mAbs intetumumab, and abituzumab target this protein which is found on some tumour cells.[6] | https://www.wikidoc.org/index.php/ITGAV | |
d164149f28ca03589a1a65a989b3595104e2cf35 | wikidoc | ITGB4 | ITGB4
Integrin, beta 4 (ITGB4) also known as CD104 (Cluster of Differentiation 104), is a human gene.
# Function
Integrins are heterodimers composed of alpha and beta subunits, that are noncovalently associated transmembrane glycoprotein receptors. Different combinations of alpha and beta polypeptides form complexes that vary in their ligand-binding specificities. Integrins mediate cell-matrix or cell-cell adhesion, and transduced signals that regulate gene expression and cell growth. This gene encodes the integrin beta 4 subunit, a receptor for the laminins. This subunit tends to associate with alpha 6 subunit and is likely to play a pivotal role in the biology of invasive carcinoma. Mutations in this gene are associated with epidermolysis bullosa with pyloric atresia. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
# Interactions
ITGB4 has been shown to interact with Collagen, type XVII, alpha 1, EIF6 and Erbin. | ITGB4
Integrin, beta 4 (ITGB4) also known as CD104 (Cluster of Differentiation 104), is a human gene.[1]
# Function
Integrins are heterodimers composed of alpha and beta subunits, that are noncovalently associated transmembrane glycoprotein receptors. Different combinations of alpha and beta polypeptides form complexes that vary in their ligand-binding specificities. Integrins mediate cell-matrix or cell-cell adhesion, and transduced signals that regulate gene expression and cell growth. This gene encodes the integrin beta 4 subunit, a receptor for the laminins. This subunit tends to associate with alpha 6 subunit and is likely to play a pivotal role in the biology of invasive carcinoma. Mutations in this gene are associated with epidermolysis bullosa with pyloric atresia. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[1]
# Interactions
ITGB4 has been shown to interact with Collagen, type XVII, alpha 1,[2][3] EIF6[4] and Erbin.[5] | https://www.wikidoc.org/index.php/ITGB4 | |
8890b64e1118da12c9b93684df16f218a0caeef8 | wikidoc | ITGB8 | ITGB8
Integrin beta-8 is a protein that in humans is encoded by the ITGB8 gene.
# Function
This gene is a member of the integrin beta chain family and encodes a single-pass type I membrane protein with a VWFA domain and four cysteine-rich repeats. This protein noncovalently binds to an alpha subunit to form a heterodimeric integrin complex. In general, integrin complexes mediate cell-cell and cell-extracellular matrix interactions and this complex plays a role in human airway epithelial proliferation. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. Additionally, it has been shown to interact with RhoGDI1 to alter the activation of Rho GTPases to promote Glioblastoma cell invasiveness. Uncoupling the αvβ8-RhoGDI1 interaction has been seen to block GBM cell invasion by hyperactivating Rho GTPases.
# Clinical significance
High expression levels of ITGB8 are associated with high angiogenic and poorly invasive glioblastoma tumors. Conversely low expression of ITGB8 correlates with highly invasive but low angiogenic tumors. | ITGB8
Integrin beta-8 is a protein that in humans is encoded by the ITGB8 gene.[1]
# Function
This gene is a member of the integrin beta chain family and encodes a single-pass type I membrane protein with a VWFA domain and four cysteine-rich repeats. This protein noncovalently binds to an alpha subunit to form a heterodimeric integrin complex. In general, integrin complexes mediate cell-cell and cell-extracellular matrix interactions and this complex plays a role in human airway epithelial proliferation. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized.[1] Additionally, it has been shown to interact with RhoGDI1 to alter the activation of Rho GTPases to promote Glioblastoma cell invasiveness. Uncoupling the αvβ8-RhoGDI1 interaction has been seen to block GBM cell invasion by hyperactivating Rho GTPases.[2]
# Clinical significance
High expression levels of ITGB8 are associated with high angiogenic and poorly invasive glioblastoma tumors. Conversely low expression of ITGB8 correlates with highly invasive but low angiogenic tumors.[3] | https://www.wikidoc.org/index.php/ITGB8 | |
3d2df295caf5ad596fd84167ecf7e1c580d51da4 | wikidoc | ITM2A | ITM2A
Integral membrane protein 2A is a protein that in humans is encoded by the ITM2A gene.
# Function
The protein encoded by this gene is involved in osteo- and chondrogenic cellular differentiation (the cells which are responsible for the development of bone and cartilage respectively).
ITM2A is also involved in activation of T-cells in the immune system and in myocyte differentiation. | ITM2A
Integral membrane protein 2A is a protein that in humans is encoded by the ITM2A gene.[1][2][3][4]
# Function
The protein encoded by this gene is involved in osteo- and chondrogenic cellular differentiation (the cells which are responsible for the development of bone and cartilage respectively).[2]
ITM2A is also involved in activation of T-cells in the immune system[5] and in myocyte differentiation.[6] | https://www.wikidoc.org/index.php/ITM2A | |
6fd843256cba087b43046a2743b711ce3ae555bc | wikidoc | ITPKA | ITPKA
Inositol-trisphosphate 3-kinase A is an enzyme that in humans is encoded by the ITPKA gene.
# Structure
ITPKA is one of three inositol-trisphosphate 3-kinase (ITP3K) genes in humans. ITP3K proteins regulate inositol phosphate metabolism by phosphorylation of the second messenger inositol 1,4,5-trisphosphate to produce Ins(1,3,4,5)P4, which is sometimes abbreviated as IP4. Structurally, ITPKA belongs to the inositol polyphosphate kinase (IPK) family. The activity of the inositol 1,4,5-trisphosphate 3-kinase is responsible for regulating the levels of a large number of inositol polyphosphates that are important in cellular signaling, most notably, inositol trisphosphate, which is the enzyme's only substrate. Both calcium/calmodulin and protein phosphorylation mechanisms control its activity. It is also a substrate for the cyclic AMP-dependent protein kinase, calcium/calmodulin- dependent protein kinase II, and protein kinase C in vitro. ITPKA and ITPKB are 68% identical in the C-terminus region The amino- terminal region of ITPKA binds filamentous actin. This property localizes the ITPKA to dendritic spines in principal neurons. ITPKA is expressed physiologically in neurons, but it is sometimes expressed in cancer cells and may contribute to processes of metastasis.
# Physiological function
ITPKA participates in learning and memory processes in neurons.
# Roles in human disease
Although ITPKA is expressed physiologically in neurons and testis, it sometimes becomes expressed in cancer cells, and the expression usually makes the cancer more aggressive.
# Relationship to F-tractin
F-tractin is amino acids 9-52 of rat ITPKA. It was later determined that amino acids 9-40 were sufficient for binding filamentous actin. When fused to a reporter, such as green fluorescent protein, It is useful for the vsualization of actin dynamics in living cells. | ITPKA
Inositol-trisphosphate 3-kinase A is an enzyme that in humans is encoded by the ITPKA gene.[1][2][3]
# Structure
ITPKA is one of three inositol-trisphosphate 3-kinase (ITP3K) genes in humans. ITP3K proteins regulate inositol phosphate metabolism by phosphorylation of the second messenger inositol 1,4,5-trisphosphate to produce Ins(1,3,4,5)P4, which is sometimes abbreviated as IP4. Structurally, ITPKA belongs to the inositol polyphosphate kinase (IPK) family. The activity of the inositol 1,4,5-trisphosphate 3-kinase is responsible for regulating the levels of a large number of inositol polyphosphates that are important in cellular signaling, most notably, inositol trisphosphate, which is the enzyme's only substrate. Both calcium/calmodulin and protein phosphorylation mechanisms control its activity. It is also a substrate for the cyclic AMP-dependent protein kinase, calcium/calmodulin- dependent protein kinase II, and protein kinase C in vitro. ITPKA and ITPKB are 68% identical in the C-terminus region The amino- terminal region of ITPKA binds filamentous actin. This property localizes the ITPKA to dendritic spines in principal neurons.[4][5][6] ITPKA is expressed physiologically in neurons, but it is sometimes expressed in cancer cells and may contribute to processes of metastasis.[7]
# Physiological function
ITPKA participates in learning and memory processes in neurons.[8][9]
# Roles in human disease
Although ITPKA is expressed physiologically in neurons and testis, it sometimes becomes expressed in cancer cells, and the expression usually makes the cancer more aggressive.[7][10]
# Relationship to F-tractin
F-tractin is amino acids 9-52 of rat ITPKA. It was later determined that amino acids 9-40 were sufficient for binding filamentous actin.[11][12] When fused to a reporter, such as green fluorescent protein, It is useful for the vsualization of actin dynamics in living cells.[13][14] | https://www.wikidoc.org/index.php/ITPKA | |
c49ea1e05dc4811000294118f64dc285a89f1ea7 | wikidoc | ITPKC | ITPKC
ITPKC is one of 3 human genes that encode for an Inositol-trisphosphate 3-kinase. This gene that has been associated with Kawasaki disease. Kawasaki disease is an acute febrile illness that involves the inflammation of blood vessels throughout the body. The majority of cases that have been diagnosed involve children under the age of 5. In untreated cases involving children, 15 to 25 percent of these cases developed coronary artery aneurysms. The overproduction of T cells may be correlated with the immune hyperactivity in Kawasaki disease.
This gene is located at chromosome 19q13.1, it codes for one of three isoenzymes. The other two enzymes being ITPKA and ITPKB. ITPKC is involved in the Ca(2+)/NFAT pathway, negatively regulating T cell activation.
A mutation in this gene occurs through a single-nucleotide polymorphism. When a mutation occurs the gene does not produce a functioning enzyme, meaning it will no longer be effective in negatively regulating T cells. When there is this reduced expression of the enzyme, ITPKC, there is a higher amount of IP3 which leads to the calcium channels being opened, and a higher amount of calcium being released. Leading to overly active T cells, and having this mutation in ITPKC is correlated to the increased risk of developing symptoms. | ITPKC
ITPKC is one of 3 human genes that encode for an Inositol-trisphosphate 3-kinase. This gene that has been associated with Kawasaki disease.[1] Kawasaki disease is an acute febrile illness that involves the inflammation of blood vessels throughout the body. The majority of cases that have been diagnosed involve children under the age of 5. In untreated cases involving children, 15 to 25 percent of these cases developed coronary artery aneurysms.[2] The overproduction of T cells may be correlated with the immune hyperactivity in Kawasaki disease.
This gene is located at chromosome 19q13.1, it codes for one of three isoenzymes. The other two enzymes being ITPKA and ITPKB. ITPKC is involved in the Ca(2+)/NFAT pathway, negatively regulating T cell activation.[3]
A mutation in this gene occurs through a single-nucleotide polymorphism. When a mutation occurs the gene does not produce a functioning enzyme, meaning it will no longer be effective in negatively regulating T cells. When there is this reduced expression of the enzyme, ITPKC, there is a higher amount of IP3 which leads to the calcium channels being opened, and a higher amount of calcium being released.[4] Leading to overly active T cells, and having this mutation in ITPKC is correlated to the increased risk of developing symptoms.[5] | https://www.wikidoc.org/index.php/ITPKC | |
f3b02de399899caa034716a230abd53689be92b1 | wikidoc | IUBMB | IUBMB
The International Union of Biochemistry and Molecular Biology (IUBMB) is an international non-governmental organisation concerned with biochemistry and molecular biology. Formed in 1955 as the International Union of Biochemistry, the union has presently 77 member countries (as of 2008).
IUBMB organizes a triennial Congress of Biochemistry and Molecular Biology, and sponsors more frequent conferences, symposia, educational activities and lectures.
It publishes standards on biochemical nomenclature, including enzyme nomenclature, in some cases jointly with the International Union of Pure and Applied Chemistry (IUPAC).
It is associated with the journals Biochemistry and Molecular Biology Education (formerly Biochemical Education), BioEssays, BioFactors, Biotechnology and Applied Biochemistry, IUBMB Life, Molecular Aspects of Medicine and Trends (journals)|Trends in Biochemical Sciences.
The current president is Angelo Azzi. Past presidents include George Kenyon, Brian F.C. Clark, Mary Osborn, Harland G. Wood, William J. Whelan, K. Yagi and Hans Kornberg. | IUBMB
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The International Union of Biochemistry and Molecular Biology (IUBMB) is an international non-governmental organisation concerned with biochemistry and molecular biology. Formed in 1955 as the International Union of Biochemistry, the union has presently 77 member countries (as of 2008).
IUBMB organizes a triennial Congress of Biochemistry and Molecular Biology, and sponsors more frequent conferences, symposia, educational activities and lectures.
It publishes standards on biochemical nomenclature, including enzyme nomenclature, in some cases jointly with the International Union of Pure and Applied Chemistry (IUPAC).
It is associated with the journals Biochemistry and Molecular Biology Education (formerly Biochemical Education), BioEssays, BioFactors, Biotechnology and Applied Biochemistry, IUBMB Life, Molecular Aspects of Medicine and Trends (journals)|Trends in Biochemical Sciences.
The current president is Angelo Azzi. Past presidents include George Kenyon, Brian F.C. Clark, Mary Osborn, Harland G. Wood, William J. Whelan, K. Yagi and Hans Kornberg. | https://www.wikidoc.org/index.php/IUBMB | |
8bb969026d9a62c5dcaee5952c8ec48c46295981 | wikidoc | IUPAP | IUPAP
The International Union of Pure and Applied Physics (IUPAP) is an international non-governmental organization devoted to the advancement of physics. It was established in 1922 and the first General Assembly was held in 1923 in Paris.
The aims of the Union are: to stimulate and promote international cooperation in physics; to sponsor suitable international meetings and to assist organizing committees; to foster the preparation and the publication of abstracts of papers and tables of physical constants; to promote international agreements on the use of symbols, units, nomenclature and standards; to foster free circulation of scientists; to encourage research and education.
The Union is governed by its General Assembly, which meets every three years. The Council is its top executive body, supervising the activities of the nineteen specialized International Commissions and the three Affiliated Commissions. The Union is composed of Members representing identified physics communities. At present 49 Members adhere to IUPAP.
IUPAP is a member of the International Council for Science (ICSU).
The SUNAMCO Commission of the IUPAP published the book entitled Symbols, Units, Nomenclature and Fundamental Constants in Physics, 1987 Revision, by E.R. Cohen and P. Giacomo which is also known as the red book, I.U.P.A.P.-25, or SUNAMCO 87-1. This book was reprinted from Physica, Vol. 146A, Nos. 1-2, p. 1 (November, 1987) . The SP Technical Research Institute of Sweden website makes the 1987 edition of the Symbols, Units, Nomenclature and Fundamental Constants in Physics available on the internet. | IUPAP
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The International Union of Pure and Applied Physics (IUPAP) is an international non-governmental organization devoted to the advancement of physics. It was established in 1922 and the first General Assembly was held in 1923 in Paris.
The aims of the Union are: to stimulate and promote international cooperation in physics; to sponsor suitable international meetings and to assist organizing committees; to foster the preparation and the publication of abstracts of papers and tables of physical constants; to promote international agreements on the use of symbols, units, nomenclature and standards; to foster free circulation of scientists; to encourage research and education.
The Union is governed by its General Assembly, which meets every three years. The Council is its top executive body, supervising the activities of the nineteen specialized International Commissions and the three Affiliated Commissions. The Union is composed of Members representing identified physics communities. At present 49 Members adhere to IUPAP.
IUPAP is a member of the International Council for Science (ICSU).
The SUNAMCO Commission of the IUPAP published the book entitled Symbols, Units, Nomenclature and Fundamental Constants in Physics, 1987 Revision, by E.R. Cohen and P. Giacomo which is also known as the red book, I.U.P.A.P.-25, or SUNAMCO 87-1. This book was reprinted from Physica, Vol. 146A, Nos. 1-2, p. 1 (November, 1987) [2]. The SP Technical Research Institute of Sweden website [3] makes the 1987 edition of the Symbols, Units, Nomenclature and Fundamental Constants in Physics available on the internet.
[4] | https://www.wikidoc.org/index.php/IUPAP | |
9412938fb8874a13121f236acf864a9b488707b9 | wikidoc | Iboga | Iboga
Iboga (Tabernanthe iboga), also known as Black bugbane, is a perennial rainforest shrub and hallucinogen, native to western Africa. Iboga stimulates the central nervous system when taken in small doses and induces visions in larger doses.
Normally growing to a height of 2 m, T. iboga may eventually grow into a small tree up to 10 m tall, given the right conditions. It has small green leaves. Its flowers are white and pink, while the elongated, oval-shaped fruit are orange. Its yellow-coloured roots contains a number of indole alkaloids, most notably ibogaine, which is found in the highest concentration in the root-bark. The root material, bitter in taste, causes an anaesthetic sensation in the mouth as well as systemic numbness to the skin.
# Traditional use
The Iboga tree is the central pillar of the Bwiti religion practiced in West-Central Africa, mainly Gabon, Cameroon and the Republic of the Congo, which utilises the alkaloid-containing roots of the plant in a number of ceremonies. Iboga is taken in massive doses by initiates when entering the religion, and on a more regular basis is eaten in smaller doses in connection with rituals and tribal dances, which is usually performed at night time. Bwitists have been subject to persecution by Catholic missionaries, who to this day are thoroughly opposed to the growing religious movement of Bwiti. Léon M'ba, before becoming the first President of Gabon in 1960, defended the Bwiti religion and the use of iboga in French colonial courts. On June 6, 2000, the Council of Ministers of the Republic of Gabon declared Tabernanthe iboga to be a national treasure.
# Addiction treatment
Outside Africa, iboga extracts as well as the purified alkaloid ibogaine are used in treating opiate addiction. The therapy may last several days and upon completion the subject is generally no longer physically dependent. One methadone patient said in the Dutch behind-the-news show Twee Vandaag that in just four days he reached a state that normally would have taken him three months, but without the agony. Evidence suggests that ibogaine may also help to interrupt addiction to alcohol and nicotine. The pharmacological effects are rather undisputed with hundreds of peer reviewed papers in support but formal clinical studies have not been completed.
# Legal status
Iboga is outlawed or restricted in Belgium, Denmark, France, Sweden, Switzerland and the United States. Root material and extracts thereof is obtainable through various European smart shops.
# Quotations
- "The Catholic church is a beautiful theory for Sunday, the iboga on the contrary is the practice of everyday living. In church, they speak of God, with iboga, you live God" (Nengue Me Ndjoung Isidore, ecumenical Bwitist religious leader) | Iboga
Iboga (Tabernanthe iboga), also known as Black bugbane, is a perennial rainforest shrub and hallucinogen, native to western Africa. Iboga stimulates the central nervous system when taken in small doses and induces visions in larger doses.
Normally growing to a height of 2 m, T. iboga may eventually grow into a small tree up to 10 m tall, given the right conditions. It has small green leaves. Its flowers are white and pink, while the elongated, oval-shaped fruit are orange. Its yellow-coloured roots contains a number of indole alkaloids, most notably ibogaine, which is found in the highest concentration in the root-bark. The root material, bitter in taste, causes an anaesthetic sensation in the mouth as well as systemic numbness to the skin.
# Traditional use
The Iboga tree is the central pillar of the Bwiti religion practiced in West-Central Africa, mainly Gabon, Cameroon and the Republic of the Congo, which utilises the alkaloid-containing roots of the plant in a number of ceremonies. Iboga is taken in massive doses by initiates when entering the religion, and on a more regular basis is eaten in smaller doses in connection with rituals and tribal dances, which is usually performed at night time. Bwitists have been subject to persecution by Catholic missionaries, who to this day are thoroughly opposed to the growing religious movement of Bwiti. Léon M'ba, before becoming the first President of Gabon in 1960, defended the Bwiti religion and the use of iboga in French colonial courts. On June 6, 2000, the Council of Ministers of the Republic of Gabon declared Tabernanthe iboga to be a national treasure.
# Addiction treatment
Outside Africa, iboga extracts as well as the purified alkaloid ibogaine are used in treating opiate addiction. The therapy may last several days and upon completion the subject is generally no longer physically dependent. One methadone patient said in the Dutch behind-the-news show Twee Vandaag that in just four days he reached a state that normally would have taken him three months, but without the agony. Evidence suggests that ibogaine may also help to interrupt addiction to alcohol and nicotine. The pharmacological effects are rather undisputed with hundreds of peer reviewed papers in support but formal clinical studies have not been completed.
# Legal status
Iboga is outlawed or restricted in Belgium, Denmark, France[1], Sweden, Switzerland and the United States. Root material and extracts thereof is obtainable through various European smart shops.[citation needed]
# Quotations
- "The Catholic church is a beautiful theory for Sunday, the iboga on the contrary is the practice of everyday living. In church, they speak of God, with iboga, you live God" (Nengue Me Ndjoung Isidore, ecumenical Bwitist religious leader) | https://www.wikidoc.org/index.php/Iboga | |
1882719a6d9070b3d2f6f05ac5e8b42c18f0e293 | wikidoc | Ichor | Ichor
In Greek mythology, ichor (Greek Template:Polytonic) is the mineral that is the Greek gods' blood, sometimes said to have been present in ambrosia or nectar. When a god was injured and bled, the ichor made his or her blood poisonous to mortals.
Ichor has also been used to mean the blood in a vampire's veins. Whereas many vampire stories and movies describe them as having reddish or dark red blood, others describe vampire blood as being different from human blood altogether—an ichor that is traditionally dark green in color.
H. P. Lovecraft often used ichor in his descriptions of other-worldly creatures, most prominently in his nightmarish detail of the chimeric remains of Wilbur Whateley, in "The Dunwich Horror".
The term ichor is often misused in fantasy contexts by authors trying to find a different word for "blood" or "ooze", to the point that it has become cliché. Author Ursula LeGuin, in "From Elfland to Poughkeepsie", calls the term "the infallible touchstone of the seventh-rate."
Ichor has also been used in science fiction as an alien substitute for blood, as in Garth Nix's book Shade's Children. Additionally, in the Dragonriders of Pern novel series, Anne McCaffrey refers to the blood of the alien (but genetically enhanced by humans) Pernese dragons as ichor. | Ichor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In Greek mythology, ichor (Greek Template:Polytonic) is the mineral[citation needed] that is the Greek gods' blood, sometimes said to have been present in ambrosia or nectar.[citation needed] When a god was injured and bled, the ichor made his or her blood poisonous to mortals.[citation needed]
Ichor has also been used to mean the blood in a vampire's veins[citation needed]. Whereas many vampire stories and movies describe them as having reddish or dark red blood, others describe vampire blood as being different from human blood altogether—an ichor that is traditionally dark green in color.
H. P. Lovecraft often used ichor in his descriptions of other-worldly creatures, most prominently in his nightmarish detail of the chimeric remains of Wilbur Whateley, in "The Dunwich Horror".
The term ichor is often misused in fantasy contexts by authors trying to find a different word for "blood" or "ooze", to the point that it has become cliché. Author Ursula LeGuin, in "From Elfland to Poughkeepsie", calls the term "the infallible touchstone of the seventh-rate."[1]
Ichor has also been used in science fiction as an alien substitute for blood, as in Garth Nix's book Shade's Children. Additionally, in the Dragonriders of Pern novel series, Anne McCaffrey refers to the blood of the alien (but genetically enhanced by humans) Pernese dragons as ichor. | https://www.wikidoc.org/index.php/Ichor | |
570d8a992999f3e1d531e57b8eeca503d2f3b414 | wikidoc | Ileum | Ileum
# Overview
In anatomy of the digestive system, the ileum is the final section of the small intestine. It is about 2-4 m long in humans, follows the duodenum and jejunum, and is separated from the cecum by the ileocecal valve (ICV). The pH in the ileum is usually between 7 and 8 (neutral or slightly alkaline).
# Function
Its function is mainly to absorb vitamin B12 and bile salts and whatever products of digestion that were not absorbed by the jejunum. The wall itself is made up of folds, each of which has many tiny finger-like projections known as villi, on its surface. In turn, the epithelial cells which line these villi possess even larger numbers of microvilli. Therefore the ileum has an extremely large surface area both for the adsorption (attachment) of enzyme molecules and for the absorption of products of digestion. The DNES (diffuse neuroendocrine system)cells that line the ileum contain the protease and carbohydrase enzymes (gastrin, secretin, cholecystokinin) responsible for the final stages of protein and carbohydrate digestion. These enzymes are present in the cytoplasm of the epithelial cells. The villi contain large numbers of capillaries which take the amino acids and glucose produced by digestion to the hepatic portal vein and the liver.
Lacteals are small lymph vessels, and are present in villi. They absorb fatty acid and glycerol, the products of fat digestion. Layers of circular and longitudinal smooth muscle enable the digested food to be pushed along the ileum by waves of muscle contractions called peristalsis.
# Differences between jejunum and ileum
There is no line of demarcation between the jejunum and the ileum. There are, however, subtle differences between the two.
- The ileum has more fat inside the mesentery than the jejunum.
- The ileum is a paler color, and tends to be of a smaller caliber as well.
- While the length of the intestinal tract contains lymphoid tissue, only the ileum has abundant Peyer's patches.
These unencapsulated lymphoid nodules contain large amounts of lymphocytes and other cells of the immune system.
# Embryology
In the fetus the ileum is connected to the navel by the vitelline duct. In roughly 3% of humans, this duct fails to close during the first seven weeks after birth, causing a condition called Meckel's diverticulum.
# Veterinary anatomy
In veterinary anatomy, the ileum is distinguished from the jejunum by being that portion of the jejunoileum that is connected to the caecum by the ileocaecal fold.
# Additional images
- Inferior ileocecal fossa.
- Arteries of cecum and vermiform process.
- Goblet cell in ileum | Ileum
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Infobox Anatomy
In anatomy of the digestive system, the ileum is the final section of the small intestine. It is about 2-4 m long in humans, follows the duodenum and jejunum, and is separated from the cecum by the ileocecal valve (ICV). The pH in the ileum is usually between 7 and 8 (neutral or slightly alkaline).
# Function
Its function is mainly to absorb vitamin B12 and bile salts and whatever products of digestion that were not absorbed by the jejunum. The wall itself is made up of folds, each of which has many tiny finger-like projections known as villi, on its surface. In turn, the epithelial cells which line these villi possess even larger numbers of microvilli. Therefore the ileum has an extremely large surface area both for the adsorption (attachment) of enzyme molecules and for the absorption of products of digestion. The DNES (diffuse neuroendocrine system)cells that line the ileum contain the protease and carbohydrase enzymes (gastrin, secretin, cholecystokinin) responsible for the final stages of protein and carbohydrate digestion. These enzymes are present in the cytoplasm of the epithelial cells. The villi contain large numbers of capillaries which take the amino acids and glucose produced by digestion to the hepatic portal vein and the liver.
Lacteals are small lymph vessels, and are present in villi. They absorb fatty acid and glycerol, the products of fat digestion. Layers of circular and longitudinal smooth muscle enable the digested food to be pushed along the ileum by waves of muscle contractions called peristalsis.
# Differences between jejunum and ileum
There is no line of demarcation between the jejunum and the ileum. There are, however, subtle differences between the two.
- The ileum has more fat inside the mesentery than the jejunum.
- The ileum is a paler color, and tends to be of a smaller caliber as well.
- While the length of the intestinal tract contains lymphoid tissue, only the ileum has abundant Peyer's patches.
These unencapsulated lymphoid nodules contain large amounts of lymphocytes and other cells of the immune system.
# Embryology
In the fetus the ileum is connected to the navel by the vitelline duct. In roughly 3% of humans, this duct fails to close during the first seven weeks after birth, causing a condition called Meckel's diverticulum.
# Veterinary anatomy
In veterinary anatomy, the ileum is distinguished from the jejunum by being that portion of the jejunoileum that is connected to the caecum by the ileocaecal fold.
# Additional images
- Inferior ileocecal fossa.
- Arteries of cecum and vermiform process.
- Goblet cell in ileum | https://www.wikidoc.org/index.php/Ileum | |
30d342fb6e3690399ab4171fe71d62b17203381f | wikidoc | Imine | Imine
An imine is a functional group or chemical compound containing a carbon-nitrogen double bond . Due to their diverse reactivity, imines are common substrates in a wide variety of transformations. An imine can be synthesised by the nucleophilic addition of an amine to a ketone or aldehyde giving a hemiaminal -C(OH)(NHR)- followed by an elimination of water to yield the imine. (see alkylimino-de-oxo-bisubstitution for a detailed mechanism) However, the equilibrium in this reaction usually lies in favor of the free carbonyl compound and amine, so that azeotrope distillation or use of a dehydrating agent such as molecular sieves is required to push the reaction in favor of imine formation.
Addition reactions with primary amines give imines that are stable under an inert atmosphere. In the presence of oxygen or water, such imines will quite readily hydrolyze or oligomerize. However, with an aryl group or certain stabilizing alkyl substituents on nitrogen, the imine formed is stable to oxygen and water and is called a Schiff base. In contrast, imine condensations using ammonia and a carbonyl compound do not lead to stable imines - the imine formed quickly oligomerizes such as in the reaction of formaldehyde and ammonia which gives hexamine instead of the corresponding imine. When a secondary amine is used, elimination of water from the hemiaminal leads to an iminium ion. This iminium ion can further react to form either an aminal, or enamine if there is an sp3-hybridized carbon in the alpha position. Addition of suitably activated carbonyl compounds to this imminium ion also leads to the corresponding Mannich base.
# Imine synthesis
- Condensation of amines with carbonyls in alkylimino-de-oxo-bisubstitution
- Condensation of carbon acids with nitroso compounds
- The rearrangement of trityl N-haloamines in the Stieglitz rearrangement
- Dehydration of hemiaminals
- By reaction of alkenes with hydrazoic acid in the Schmidt reaction
# Imine reactions
- An imine can be reduced to an amine.
- An imine can be hydrolysed with water to the corresponding amine and carbonyl compound.
- An imine reacts with an amine to an aminal, see for example the synthesis of cucurbituril.
- An imine reacts with dienes in the Aza Diels-Alder reaction to a tetrahydropyridine.
- An imine can be oxidized with meta-chloroperoxybenzoic acid (mCPBA) to give an oxaziridine
- An aromatic imine reacts with an enol ether to a quinoline in the Povarov reaction.
- A tosylimine reacts with an α,β-unsaturated carbonyl compound to an allylic amine in the Aza-Baylis-Hillman reaction.
- Imines are intermediates in the alkylation of amines with formic acid in the Eschweiler-Clarke reaction.
- A rearrangement in carbohydrate chemistry involving an imine is the Amadori rearrangement.
- A methylene transfer reaction of an imine by an unstabilised sulphonium ylide can give an aziridine system.
# Amidates
imidates (also known as imino ethers) (R-N=C(OR)R) are imines with an oxygen atom connected to carbon. These compounds find use in organic synthesis as building blocks and intermediates for example in the Mumm rearrangement and the Overman rearrangement. An example of an imidate is benzyl 2,2,2-trichloroacetimidate used to protect an alcohol as a benzyl ether with release of trichloroacetamide.
Amidates are the corresponding amide enolates: R-N=C(O-)R and find use as ligands. | Imine
An imine is a functional group or chemical compound containing a carbon-nitrogen double bond [1]. Due to their diverse reactivity, imines are common substrates in a wide variety of transformations. An imine can be synthesised by the nucleophilic addition of an amine to a ketone or aldehyde giving a hemiaminal -C(OH)(NHR)- followed by an elimination of water to yield the imine. (see alkylimino-de-oxo-bisubstitution for a detailed mechanism) However, the equilibrium in this reaction usually lies in favor of the free carbonyl compound and amine, so that azeotrope distillation or use of a dehydrating agent such as molecular sieves is required to push the reaction in favor of imine formation.
Addition reactions with primary amines give imines that are stable under an inert atmosphere. In the presence of oxygen or water, such imines will quite readily hydrolyze or oligomerize. However, with an aryl group or certain stabilizing alkyl substituents on nitrogen, the imine formed is stable to oxygen and water and is called a Schiff base. In contrast, imine condensations using ammonia and a carbonyl compound do not lead to stable imines - the imine formed quickly oligomerizes such as in the reaction of formaldehyde and ammonia which gives hexamine instead of the corresponding imine. When a secondary amine is used, elimination of water from the hemiaminal leads to an iminium ion. This iminium ion can further react to form either an aminal, or enamine if there is an sp3-hybridized carbon in the alpha position. Addition of suitably activated carbonyl compounds to this imminium ion also leads to the corresponding Mannich base.
# Imine synthesis
- Condensation of amines with carbonyls in alkylimino-de-oxo-bisubstitution
- Condensation of carbon acids with nitroso compounds
- The rearrangement of trityl N-haloamines in the Stieglitz rearrangement
- Dehydration of hemiaminals [2]
- By reaction of alkenes with hydrazoic acid in the Schmidt reaction
# Imine reactions
- An imine can be reduced to an amine.
- An imine can be hydrolysed with water to the corresponding amine and carbonyl compound.
- An imine reacts with an amine to an aminal, see for example the synthesis of cucurbituril.
- An imine reacts with dienes in the Aza Diels-Alder reaction to a tetrahydropyridine.
- An imine can be oxidized with meta-chloroperoxybenzoic acid (mCPBA) to give an oxaziridine
- An aromatic imine reacts with an enol ether to a quinoline in the Povarov reaction.
- A tosylimine reacts with an α,β-unsaturated carbonyl compound to an allylic amine in the Aza-Baylis-Hillman reaction.
- Imines are intermediates in the alkylation of amines with formic acid in the Eschweiler-Clarke reaction.
- A rearrangement in carbohydrate chemistry involving an imine is the Amadori rearrangement.
- A methylene transfer reaction of an imine by an unstabilised sulphonium ylide can give an aziridine system.
# Amidates
imidates (also known as imino ethers) (R-N=C(OR)R) are imines with an oxygen atom connected to carbon. These compounds find use in organic synthesis as building blocks and intermediates for example in the Mumm rearrangement and the Overman rearrangement. An example of an imidate is benzyl 2,2,2-trichloroacetimidate used to protect an alcohol as a benzyl ether with release of trichloroacetamide.
Amidates are the corresponding amide enolates: R-N=C(O-)R and find use as ligands. | https://www.wikidoc.org/index.php/Imine | |
e6ce4aa41a62e6505fc4475010530dcecb96513a | wikidoc | Nerve | Nerve
# Overview
A nerve is an enclosed, cable-like bundle of axons (the long, slender projection of a neuron). Neurons are sometimes called nerve cells, though this term is technically imprecise since many neurons do not form nerves, and nerves also include the glial cells that ensheath the axons in myelin.
# Anatomy
Nerves are part of the peripheral nervous system. Afferent nerves convey sensory signals to the central nervous system, for example from skin or organs, while efferent nerves conduct stimulatory signals from the central nervous system to the muscles and glands. Afferent and efferent nerves are often arranged together, forming mixed nerves. The median nerve controls motor and sensory function in the hand.
Each peripheral nerve is covered externally by a dense sheath of connective tissue, the epineurium. Underlying this is a layer of flat cells forming a complete sleeve, the perineurium. Perineurial septa extend into the nerve and subdivide it into several bundles of fibres. Surrounding each such fibre is the endoneurial sheath. This is a tube which extends, unbroken, from the surface of the spinal cord to the level at which the axon synapses with its muscle fibres or ends in sensory endings. The endoneurial sheath consists of an inner sleeve of material called the glycocalyx and an outer, delicate, meshwork of collagen fibres. Peripheral nerves are richly supplied with blood.
Most nerves connect to the middle systems through the spinal cord. The twelve cranial nerves, however, connect directly to parts of the brain. Spinal nerves are given letter-number combinations according to the vertebra through which they connect to the spinal column. Cranial nerves are assigned numbers, usually expressed as Roman numerals from I to XII. In addition, most nerves and major branches of nerves have descriptive names. Inside the central nervous system, bundles of axons are termed tracts rather than nerves.
The signals that nerves carry, sometimes called nerve impulses, are also known as action potentials: rapidly (up to 120 m/s) traveling electrical waves, which begin typically in the cell body of a neuron and propagate rapidly down the axon to its tip or "terminus." The signals cross over from the terminus to the adjacent neurotransmitter receptor through a gap called the synapse. Motor neurons innervate or activate muscles groups. The nerve system runs through the spinal cord.
# Clinical importance
Damage to nerves can be caused by physical injury, swelling (e.g. carpal tunnel syndrome), autoimmune diseases (e.g. Guillain-Barré syndrome), infection (neuritis), diabetes, or failure of the blood vessels surrounding the nerve. Pinched nerves occur when pressure is placed on a nerve, usually from swelling due to an injury or pregnancy. Nerve damage or pinched nerves are usually accompanied by pain, numbness, weakness, or paralysis. Patients may feel these symptoms in areas far from the actual site of damage, a phenomenon called referred pain. Referred pain occurs because when a nerve is damaged, signaling is defective from all parts of the area which the nerve receives input, not just the site of the damage.
Neurologists usually diagnose disorders of the nerves by a physical examination, including the testing of reflexes, walking and other directed movements, muscle weakness, proprioception, and the sense of touch. This initial exam can be followed with tests such as nerve conduction study and electromyography (EMG). | Nerve
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A nerve is an enclosed, cable-like bundle of axons (the long, slender projection of a neuron). Neurons are sometimes called nerve cells, though this term is technically imprecise since many neurons do not form nerves, and nerves also include the glial cells that ensheath the axons in myelin.
# Anatomy
Nerves are part of the peripheral nervous system. Afferent nerves convey sensory signals to the central nervous system, for example from skin or organs, while efferent nerves conduct stimulatory signals from the central nervous system to the muscles and glands. Afferent and efferent nerves are often arranged together, forming mixed nerves. The median nerve controls motor and sensory function in the hand.
Each peripheral nerve is covered externally by a dense sheath of connective tissue, the epineurium. Underlying this is a layer of flat cells forming a complete sleeve, the perineurium. Perineurial septa extend into the nerve and subdivide it into several bundles of fibres. Surrounding each such fibre is the endoneurial sheath. This is a tube which extends, unbroken, from the surface of the spinal cord to the level at which the axon synapses with its muscle fibres or ends in sensory endings. The endoneurial sheath consists of an inner sleeve of material called the glycocalyx and an outer, delicate, meshwork of collagen fibres. Peripheral nerves are richly supplied with blood.
Most nerves connect to the middle systems through the spinal cord. The twelve cranial nerves, however, connect directly to parts of the brain. Spinal nerves are given letter-number combinations according to the vertebra through which they connect to the spinal column. Cranial nerves are assigned numbers, usually expressed as Roman numerals from I to XII. In addition, most nerves and major branches of nerves have descriptive names. Inside the central nervous system, bundles of axons are termed tracts rather than nerves.
The signals that nerves carry, sometimes called nerve impulses, are also known as action potentials: rapidly (up to 120 m/s) traveling electrical waves, which begin typically in the cell body of a neuron and propagate rapidly down the axon to its tip or "terminus." The signals cross over from the terminus to the adjacent neurotransmitter receptor through a gap called the synapse. Motor neurons innervate or activate muscles groups. The nerve system runs through the spinal cord.
# Clinical importance
Damage to nerves can be caused by physical injury, swelling (e.g. carpal tunnel syndrome), autoimmune diseases (e.g. Guillain-Barré syndrome), infection (neuritis), diabetes, or failure of the blood vessels surrounding the nerve. Pinched nerves occur when pressure is placed on a nerve, usually from swelling due to an injury or pregnancy. Nerve damage or pinched nerves are usually accompanied by pain, numbness, weakness, or paralysis. Patients may feel these symptoms in areas far from the actual site of damage, a phenomenon called referred pain. Referred pain occurs because when a nerve is damaged, signaling is defective from all parts of the area which the nerve receives input, not just the site of the damage.
Neurologists usually diagnose disorders of the nerves by a physical examination, including the testing of reflexes, walking and other directed movements, muscle weakness, proprioception, and the sense of touch. This initial exam can be followed with tests such as nerve conduction study and electromyography (EMG). | https://www.wikidoc.org/index.php/Innervate | |
0e95b0a4cca4374ab3d7aaa07feb130af8f38cbd | wikidoc | Venom | Venom
Venom (literally, poison of animal origin) is any of a variety of toxins used by certain types of animals, for the purpose of defense and hunting. Generally, venom is injected while other toxins are absorbed by ingestion or through the skin.
The animals most widely known to use venom are snakes, some species of which inject venom into their prey through hollow fangs; spiders and centipedes, which also inject venom through fangs; scorpions and stinging insects, which inject venom with a sting (which is a modified egg-laying device - the ovipositor). There are also many caterpillars that have defensive venom glands associated with specialized bristles on the body, known as urticating hairs, some of which can be lethal to humans (e.g., the Lonomia moth). Venom is also found in other reptiles besides snakes such as the gila monster, and mexican beaded lizard. Other insects, such as true bugs , also produce venom. Venom can also be found in some fish, such as the cartilaginous fishes: stingrays, sharks, and chimaeras and the teleost fishes, which include: monognathus eels, catfishes, stonefishes and waspfishes, scorpionfishes and lionfishes, gurnard perches, rabbitfishes, surgeonfishes, scats, stargazers, weevers, carangids, saber-toothed blenny, and toadfish. In fact, recent studies have shown that there are more venomous ray-finned fishes than all other venomous vertebrates combined. Additionally, there are many other venomous invertebrates, including jellyfish, cone snails, bees, wasps and ants. The Box jellyfish is widely considered the most venomous creature in the world. Some mammals are also venomous, including solenodons, shrews, the slow loris, and the male platypus.
Because they are tasked to defend their hives and food stores, bees synthesize and employ an acidic venom (apitoxin) to cause pain in those that they sting, whereas wasps use a chemically different venom designed to paralyze prey, so it can be stored alive in the food chambers of their young. The use of venom is much more widespread than just these examples, of course.
It is important to note the difference between organisms that are "venomous" and "poisonous", two commonly confused terms with regards to plant and animal life. Venomous, as stated above, refers to animals that inject venom into their prey as a self-defense mechanism. Poisonous, on the other hand, describes plants or animals that are harmful when consumed or touched. One species of bird, the hooded pitohui, although not venomous, is poisonous, secreting a neurotoxin on to its skin and feathers. The slow loris, a primate, blurs the boundary between poisonous and venomous; it has poison secreting patches on the inside of its elbows which it is believed to smear on its young to prevent them from being eaten. However, it will also lick these patches, giving it a venomous bite.
# Snake venom
Snake venom is produced by glands below the eye and delivered to the victim through tubular or channeled fangs. Snake poisons contain a variety of peptide toxins. Snakes use their venom principally for hunting, though the threat of being bitten serves also as a defense. Snake bites cause a variety of symptoms including pain, swelling, tissue damage, low blood pressure, convulsions, and hemorrhaging (varying by the species of snake).
Doctors treat victims of a venomous bite with antivenom, which is created by dosing an animal such as a sheep, horse, goat, or rabbit with a small amount of the targeted venom. The immune system of the subject animal responds to the dose, producing antibodies against the venom's active molecule, which can then be harvested from the animal's blood and applied to treat envenomation in others. This treatment may be effective for a given person only a limited number of times, however, as that person will ultimately develop antibodies to neutralize the foreign animal antibodies injected into him. Even if that person doesn't suffer a serious allergic reaction to the antivenom, his own immune system can destroy the antivenom, before the antivenom can destroy the venom. Though most people never require one treatment of antivenom in their lifetime, let alone several, people who work with snakes or other venomous animals may. Fortunately, these people often develop antibodies of their own against the venom of whatever animals they handle, and thereby are immune without assistance of exogenous antibodies. | Venom
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Venom (literally, poison of animal origin) is any of a variety of toxins used by certain types of animals, for the purpose of defense and hunting. Generally, venom is injected while other toxins are absorbed by ingestion or through the skin.
The animals most widely known to use venom are snakes, some species of which inject venom into their prey through hollow fangs; spiders and centipedes, which also inject venom through fangs; scorpions and stinging insects, which inject venom with a sting (which is a modified egg-laying device - the ovipositor). There are also many caterpillars that have defensive venom glands associated with specialized bristles on the body, known as urticating hairs, some of which can be lethal to humans (e.g., the Lonomia moth). Venom is also found in other reptiles besides snakes such as the gila monster, and mexican beaded lizard. Other insects, such as true bugs [2], also produce venom. Venom can also be found in some fish, such as the cartilaginous fishes: stingrays, sharks, and chimaeras and the teleost fishes, which include: monognathus eels, catfishes, stonefishes and waspfishes, scorpionfishes and lionfishes, gurnard perches, rabbitfishes, surgeonfishes, scats, stargazers, weevers, carangids, saber-toothed blenny, and toadfish. In fact, recent studies have shown that there are more venomous ray-finned fishes than all other venomous vertebrates combined. Additionally, there are many other venomous invertebrates, including jellyfish, cone snails, bees, wasps and ants. The Box jellyfish is widely considered the most venomous creature in the world.[3] Some mammals are also venomous, including solenodons, shrews, the slow loris, and the male platypus.
Because they are tasked to defend their hives and food stores, bees synthesize and employ an acidic venom (apitoxin) to cause pain in those that they sting, whereas wasps use a chemically different venom designed to paralyze prey, so it can be stored alive in the food chambers of their young. The use of venom is much more widespread than just these examples, of course.
It is important to note the difference between organisms that are "venomous" and "poisonous", two commonly confused terms with regards to plant and animal life. Venomous, as stated above, refers to animals that inject venom into their prey as a self-defense mechanism. Poisonous, on the other hand, describes plants or animals that are harmful when consumed or touched. One species of bird, the hooded pitohui, although not venomous, is poisonous, secreting a neurotoxin on to its skin and feathers. The slow loris, a primate, blurs the boundary between poisonous and venomous; it has poison secreting patches on the inside of its elbows which it is believed to smear on its young to prevent them from being eaten. However, it will also lick these patches, giving it a venomous bite.
# Snake venom
Snake venom is produced by glands below the eye and delivered to the victim through tubular or channeled fangs. Snake poisons contain a variety of peptide toxins. Snakes use their venom principally for hunting, though the threat of being bitten serves also as a defense. Snake bites cause a variety of symptoms including pain, swelling, tissue damage, low blood pressure, convulsions, and hemorrhaging (varying by the species of snake).
Doctors treat victims of a venomous bite with antivenom, which is created by dosing an animal such as a sheep, horse, goat, or rabbit with a small amount of the targeted venom. The immune system of the subject animal responds to the dose, producing antibodies against the venom's active molecule, which can then be harvested from the animal's blood and applied to treat envenomation in others. This treatment may be effective for a given person only a limited number of times, however, as that person will ultimately develop antibodies to neutralize the foreign animal antibodies injected into him. Even if that person doesn't suffer a serious allergic reaction to the antivenom, his own immune system can destroy the antivenom, before the antivenom can destroy the venom. Though most people never require one treatment of antivenom in their lifetime, let alone several, people who work with snakes or other venomous animals may. Fortunately, these people often develop antibodies of their own against the venom of whatever animals they handle, and thereby are immune without assistance of exogenous antibodies. | https://www.wikidoc.org/index.php/Insect_venom | |
b9f44c85e9f47ce0bbf31b7d43f1a8e469145b99 | wikidoc | JADE1 | JADE1
JADE1 is a protein that in humans is encoded by the JADE1 gene.
# Family
A small family of proteins named Gene for Apoptosis and Differentiation (JADE) includes three members encoded by individual genes: Plant Homeo-domain-17 (PHF17, JADE1), PHF16 (JADE3), and PHF15 (JADE2). All JADE family proteins bear two notable mid molecule domains: the canonical Plant Homeo-domain (PHD) zinc finger and extended PHD-like zinc finger. JADE1 therefore is classified as a member of the PHD protein family. There are two known protein products of the PHF17 gene, the full length JADE1 (JADE1L) and its splice variant missing the C-terminal fragment also called short isoform (JADE1S).
# Discovery
Nagase et al. cloned and sequenced 100 individual cDNAs from fetal brain cDNA library, including clone KIAA1807 which was designated PHF17. The predicted 702-amino acid protein product of that clone was similar to the human zinc finger protein BR140 (BRPF1). Based on sequence database analysis the study suggested that PHF17 may function in nucleic acid managing pathway. Using yeast two hybrid pull down approach to search for new partners of protein product of the Von Hippel Lindau gene (pVHL) another study identified cDNA which matched to KIAA1807 clone. The protein product of that cDNA was given name JADE1 (Jade-1, PHF17). The deduced 509 amino acid long protein product of JADE1 cDNA was further confirmed as physical partner of pVHL. In a genetic screen study searching for genes involved in embryogenesis, the mouse orthologue of JADE1 was identified. That study, provided first characterization of the JADE1 gene and defined novel JADE family. The study yielded mice with knock out of JADE1 gene.
Jade1 transcripts in both humans and mice undergo alternative splicing and polyadenylation producing two major transcripts, the full length 6 kb mRNA and 3.6 kb mRNA. Two resultant protein products of the JADE1 gene were designated JADE1S for the short (which is same as(3)) and JADE1L for the long isoform. Several minor transcripts are also detected. The database analysis revealed two additional JADE1 paralogues and members of JADE family, JADE2, and JADE3. JADE3 is identical to E9 protein identified in an earlier independent study which suggested role in apoptosis for PHF16/JADE3/E9 in breast cancer cells.
JADE1 has been mapped to chromosome 4 (4q26-q27). JADE1 is conserved and its orthologues have been found or predicted in most every metazoan. Gene structure and sequences, variants, conservation, orthologues and paralogs, JADE1 phylogenetic tree and large scale screening of JADE1 tissue expression can be found in several extensive databases (; ).
# Structure
The full length JADE1 polypeptide bears one canonical and one extended PHD zinc finger domains. Other domains include the N-terminal candidate PEST domain, Enhancer of polycomb-like domain and the C-terminal nuclear localization (NLS) signal (prosite.expasy.org). JADE1 protein is a target for post translational modifications, including phosphorylation (Fig 1
). Six amino acid residues were identified to be phosphorylated in cell cycle-dependent manner via Aurora A kinase pathway. JADE1 is a target of phosphorylation by Casein kinase 2 (CK2). In addition, multiple phosphorylation sites are found by high throughput screening approaches and in silico analysis. Summary schematic for JADE1L and JADE1S proteins phosphorylation sites with references are found in.
Proteins bearing in tandem canonical and extended PHD fingers form a small subfamily within the large PHD protein family (www.genenames.org). Other proteins bearing tandem of PHD fingers and related to JADE1 include proteins that are components of chromatin binding and modifying complexes BRPF1, BRPF3, BRD1. The crystal structure of JADE1 PHD domains has not been solved. Canonical PHD finger motif has signature C4HC3, represents relatively small, stable structure, and is distinct from the C3HC4 type RING finger. PHD domains are able to recognize and bind specific methylated lysine of histone H3, which defined these domains as epigenetic histone code readers. Reviews describing structure and properties of PHD fingers in depth are available.
# Cellular function
JADE1 proteins are multifunctional and interact with several protein partners.
## Histone acetylation
Function of JADE1 in histone acetylation and transcription activation which required the second extended PHD zinc finger was reported in 2004(16). JADE1 dramatically increases levels of acetylated histone H4 within chromatin, but not histone H3, a specificity characteristic to the MYST family HAT TIP60 and HBO1. TIP60 physically associates with JADE1 and augments JADE1 HAT function in live cells. TIP60 and JADE1 mutually stabilized each other. Transcriptional and HAT activities of JADE1 require PHD2. Results suggest the chromatin targeting role for JADE1 PHD2. In addition, PHD2 of JADE1 binds the N-terminal tail of histone H3 within chromatin context irrespective of methylation status.
Studies analyzing native complexes of INhibitor of Growth (ING) PHD finger family of proteins revealed that ING4 and ING5 proteins are associated with JADE1S and HAT HBO1, while ING3 is associated with EPC1 (JADE1 homolog), TIP60 (HBO1 homolog) and several other partners. Both complexes also included a small Eaf6 protein. The biochemical and in silico analysis of complexes formed by HBO1 and TIP60 suggested common architecture and supported the role for JADE1 in bulk histone H4 acetylation. Characterization of JADE1 and HBO1 functional interactions show structural and functional similarities between the complexes(16, 19). Similarly to TIP60, JADE1 and HBO1 mutually stabilize each other. JADE1 binds to and enables HBO1 to enhance global histone H4 acetylation, which requires intact PHD2 finger.
Similarly to HBO1, JADE1 is responsible for bulk histone H4 acetylation in cultured cells. H4K5, H4K12, and most likely H4K8 are targets of JADE1-dependent acetylation in cultured cells and in vivo.
Several potential transcription targets of JADE1 have been suggested from experiments using screening approaches. According to screening genomic analysis done by ChIP-chip assay JADE1L complex is found mainly along the coding regions of many genes and JADE1L abundance correlates mostly with H3K36me3 histone mark. JADE1L over expression correlates with increased quantities of H4acK8 in the coding region of many genes. The two PHD zinc fingers of JADE1 appear to bind preferentially non-methylated N-terminal peptide of histone.
JADE1 isoforms assemble at least two different complexes, JADE1L-HBO1-ING4/5 and JADE1S-HBO1 complex. Due to the lack of the C-terminal fragment, JADE1S is incapable of binding ING4/5 partners. A small less characterized protein Eaf6 is also another component of JADE1 complexes.
## Cell cycle
Acetylation of N-terminal fragments of bulk histone H4 has been known to correlate with DNA synthesis and cell division. Several studies support cell cycle role for JADE1 linked to HBO1 pathway. Both, JADE1 and HBO1 are independently required for the acetylation of bulk histone H4 in cultured cells. The depletion of JADE1 proteins by siRNA results in 1) decreased levels of histone H4 bulk acetylation; 2) slower rates of DNA synthesis in cultured cells; 3) decreased levels of the total and chromatin-bound HBO1; 4) abrogation of chromatin recruitment of MCM7. Agreeing with these results, JADE1L over-expression increases chromatin-bound MCM3 protein. The effects of JADE1 depletion on DNA replication events are similar to those described originally for HBO1 and suggests adaptor role for JADE1 in HBO1-mediated cell cycle regulation.
JADE1 role in DNA damage has been suggested. A recently discovered non-coding RNA lncRNA-JADE regulates JADE1 expression and provides a functional link between the DNA damage response (DDR) and bulk histone H4 acetylation. Results support role in DNA synthesis linked to histone H4 acetylation. In cultured cells knock down of lncRNA-JADE increased cells sensitivity to DNA damaging drugs. In mice tumor xenograft model, the knock down of lncRNA-JADE inhibited xenograft mammary tumor growth. In a pilot human study, higher levels of lncRNA-JADE as well as JADE1 protein were detected in breast cancer tissues compared to normal tissues. Lastly, the higher levels of JADE1 protein inversely correlated with survival rates of patients with breast cancer. The study suggests that lncRNA-JADE might contribute to breast tumorigenesis, and that JADE1 protein mediates at least part of this effect.
JADE1 and cytokinesis. JADE1S negatively regulates cytokinesis of the epithelial cell cycle, a function specific to the small isoform. First report that suggested JADE1 function in G2/M/G1 transition showed that during the late G2 phase, JADE1S undergoes phosphorylation linked to its dissociation from chromatin into the cytoplasm. Mass Spectral analysis identified that total of six individual amino acid residues are phosphorylated by a mitotic kinase. Based on pharmacological analysis, JADE1 phosphorylation and compartmentalization is regulated by Aurora A and Aurora B pathways. Other kinases have been reported and may play a role. Upon completion of mitosis around telophase, the main pool of the JADE1S protein undergoes de-phosphorylation and re-associates with apparently condensing chromatin inside the reformed nuclei. A discrete pool of JADE1S associates with the cleavage furrow and subsequently appears in the midbody of the cytokinetic bridge. Only JADE1S, but not JADE1L or HBO1 was found in the midbody of the cells undergoing cytokinesis. The spatial regulation of JADE1S during the cell division suggested role in G2/M to G1 transition, which includes cytokinesis and final abscission.
Cytokinesis is the final step of cell cycle which controls fidelity of division of cellular content, including cytoplasm, membrane, and chromatin. Cytokinetic bridge is severed during the final abscission which occurs near the midbody and may take up to 2 hours. Cytokinesis and final abscission are tightly controlled by regulatory protein complexes and checkpoint proteins. The number of reports concerning cytokinesis control has been growing over the past decade.
JADE1 role in cytokinesis was demonstrated by use of several functional assays and cell culture models. DNA profiling by FACS showed that JADE1S depletion facilitated rates of G1-cells accumulation in synchronously dividing HeLa cells. The depletion of JADE1S protein in asynchronously dividing cells decreased the proportion of cytokinetic cells, and increased the proportion of multi-nuclear cells. The data demonstrated that JADE1 negatively controls cytokinesis, presumably by contributing to cytokinesis delay. JADE1 down-regulation increased number of multi-nuclear cells indicative of failed cytokinesis, while JADE1S moderate overexpression augmented the number of cytokinetic cells indicative of cytokinetic delay. Inhibition of Aurora B kinase by specific small molecule drugs resulted in the release of JADE1S-mediated cytokinetic delay and allowed progression of abscission. Since Aurora B is a key regulator of the NoCut, JADE1S is likely to regulate cytokinesis at the abscission checkpoint control.
JADE1S but not JADE1L or HBO1 was found in centrosomes of dividing cells throughout the cell cycle, and neither of these proteins was found in cilia. In contrast, another study reported JADE1 localization to the cilia and centrosome. The study did not communicate on JADE1 isoform specificity. Centrosomes are the cytoskeleton nucleation centers. Centrosome signaling contributes to the definition of cell shape, motility, orientation, polarity, division plane and to the fidelity of sister chromosome separation during mitosis and cytokinesis.
## pVHL
The first protein partner of JADE1S has been identified in 2002 in a study searching for new partners of the pVHL, which is a tumor suppressor. A few follow up studies characterized binding and provided some insights on functional interactions of JADE1-pVHL.
The human pVHL is mutated in von Hippel–Lindau hereditary disease, and in majority of sporadic clear cell renal carcinomas. Properties and function of pVHL have been investigated for many decades and extensive literature is available. One of the better known functions of pVHL is to mediate protein ubiquitination and proteosomal degradation. As a component of ubiquitin ligase E3 complex pVHL binds and targets several known factors, including HIF1a and HIF2a for ubiquitination. Mechanism of HIF1a activation by hypoxia and role of pVHL in this pathway has been reported over a decade ago. The VHL protein has been intensely studied and the link of naturally occurring mutations to cancers established. Other causative HIF-1a-independent pVHL pathways have been considered. The pVHL-JADE1S physical interaction was identified by yeast-two hybrid screening analysis and was further confirmed biochemically. Co-transfection of pVHL increased JADE1S protein half-life and abundance, suggesting potential positive relationship. Certain pVHL cancer-derived truncations but not point mutations diminished pVHL-JADE1 stabilization function, suggesting link to pVHL-associated cancers.
Molecular pathways and cellular significance of JADE1-pVHL interactions are not well understood. Single study describing JADE1S intrinsic ubiquitin-ligase activity and ubiquitination of beta-catenin has been reported in year 2008. Based on that study a model has been proposed that pVHL regulates beta-catenin through JADE1, and PHD zinc fingers are required for this activity.
## Apoptosis
JADE1S function in apoptosis has been proposed but the mechanisms remain elusive and results are hard to reconcile. According to studies, JADE1 overexpression slows rates of cellular growth and induces cell cycle arrest protein p21. Several attempts to establish dependable cell lines stably expressing JADE1S protein have not been successful, presumably due to the negative cells self-selection. Contrary to that, another study shows that JADE1 downregulation decreased rates of DNA synthesis in synchronously dividing cells. According to indirect immunofluorescence and microscopy analysis of cultured cells, cultured cells overload with JADE1 protein causes cell toxicity and side effects. Cells undergo morphological changes that do not resemble apoptosis but suggest severely impaired cell cycle including dyeing cells with abnormal shapes and large, multi-lobular nuclei. Based on JADE1S-mediated regulation of cell cycle other interpretations are considered: JADE1 overload might cause prolonged NoCut and stalled cytokinesis or severe cell cycle misbalance rather than direct transcription activation of apoptosis.
# Biological role
The biological role of JADE1 has not been elucidated. Limited number of publications addresses this question using mice models. The most comprehensive study which was published in 2003, identified mice orthologue of human JADE1, Jade1, and investigated Jade1 expression during mice embryogenesis. Searching for developmentally regulated genes the authors used gene trap screen analysis and identified mouse Jade1 as gene strongly regulated during embryogenesis. Insertion of the vector into the third intron of the Jade1 gene lead to the production of a 47-amino-acid truncated protein. The gene trap insertional mutation resulted in Jade1-beta-galactosidase reporter fusion product and Jade1 null allele. While the homozygotes for the gene trap integration did not produce strong developmental phenotype, the fusion product revealed Jade1 gene spatial-temporal expression in mouse embryonic cells and tissues of developing embryo up to 15.5-d.p.c. In addition the study reports experimental and in silico comparative analysis of Jade1 mRNA transcripts, Jade1 gene structure and analysis of Jade1 protein orthologues from mouse human and zebra fish.
Jade1 expression was detected in extraembryonic ectoderm and trophoblast, which are placental components important for vasculogenesis, as well as in sites enriched with multipotent or tissue-specific progenitors, including neural progenitors(2). The dynamics of Jade1 reporter expression in these areas indicates the involvement in the determination and elongation of anterior posterior axis, an important point of the study). The potential role for human JADE1 in the renewal of embryonic stem cell and embryonal carcinoma cell cultures was suggested in another screening study which showed that, in cultured stem cells activation of stem cell transcription factor OCT4 pathway upregulated JADE1 gene expression along with stem cell factors NANOG, PHC1, USP44 and SOX2.
Role of JADE1 in epithelial cell proliferation was addressed in a murine model of acute kidney injury and regeneration. Expression patterns and dynamics of HBO1-JADE1S/L were examined in regenerating tubular epithelial cells. Ischemia and reperfusion injury resulted in an initial decrease in JADE1S, JADE1L, and HBO1 protein levels, which returned to the baseline during renal recovery. Expression levels of HBO1 and JADE1S recovered as cell proliferation rate reached maximum, whereas JADE1L recovered after bulk proliferation had diminished. The temporal expression of JADE1 correlated with the acetylation of histone H4 (H4K5 and H4K12) but not that of histone H3 (H4K14), suggesting that the JADE1-HBO1 complex specifically marks H4 during epithelial cell proliferation. The results of the study implicate JADE1-HBO1 complex in acute kidney injury and suggest distinct roles for JADE1 isoforms during epithelial cell recovery.
# Disease associations
Role of JADE1 in human disease has not been elucidated. A recent study searched for novel submicroscopic genetic changes in myelofibrosis, which is a bone marrow cancer. The study identified seven novel deletions and translocations in small cohort of patients with primary myelofibrosis. JADE1 and the adjacent gene called Sodium channel and clathrin linker 1 (SCLT1) were significantly modified. As a result of mutation, JADE1 gene has deletions of intron 5-6 and exons 6-11, which would produce JADE1 missing a large chunk of protein starting from the PHD zinc finger. The relevance to pathogenesis is under investigation.
In a handful of pilot studies JADE1 expression was examined in colon cancers and renal carcinomas. The results in these studies do not always reconcile. The results of some studies are generated mostly from the histochemical analysis of tumor specimens using JADE1 antibody with uncharacterized specificities towards JADE1 in general, and JADE1S or JADE1L in particular. Results of study using in silico microarray algorithm analysis shows, that PHF17 mRNA may play a role in the development of pancreatic cancer. These promising lines of investigations require further controls and additional assessments.
# Interactions
Several proteins interact with JADE1, including: pVHL, TIP60, HBO1, ING4, ING5, ß-catenin, NPHP4.
# Notes | JADE1
JADE1 is a protein that in humans is encoded by the JADE1 gene.[1][2][3][4]
# Family
A small family of proteins named Gene for Apoptosis and Differentiation (JADE)[2] includes three members encoded by individual genes: Plant Homeo-domain-17 (PHF17, JADE1), PHF16 (JADE3), and PHF15 (JADE2). All JADE family proteins bear two notable mid molecule domains: the canonical Plant Homeo-domain (PHD) zinc finger and extended PHD-like zinc finger. JADE1 therefore is classified as a member of the PHD protein family. There are two known protein products of the PHF17 gene, the full length JADE1 (JADE1L) and its splice variant missing the C-terminal fragment also called short isoform (JADE1S).
# Discovery
Nagase et al. cloned and sequenced 100 individual cDNAs from fetal brain cDNA library, including clone KIAA1807 which was designated PHF17.[5] The predicted 702-amino acid protein product of that clone was similar to the human zinc finger protein BR140 (BRPF1).[6] Based on sequence database analysis the study suggested that PHF17 may function in nucleic acid managing pathway.[5] Using yeast two hybrid pull down approach to search for new partners of protein product of the Von Hippel Lindau gene (pVHL) another study identified cDNA which matched to KIAA1807 clone.[7] The protein product of that cDNA was given name JADE1 (Jade-1, PHF17).[7] The deduced 509 amino acid long protein product of JADE1 cDNA was further confirmed as physical partner of pVHL.[7] In a genetic screen study searching for genes involved in embryogenesis, the mouse orthologue of JADE1 was identified.[2] That study, provided first characterization of the JADE1 gene and defined novel JADE family. The study yielded mice with knock out of JADE1 gene.
Jade1 transcripts in both humans and mice undergo alternative splicing and polyadenylation producing two major transcripts, the full length 6 kb mRNA and 3.6 kb mRNA.[2] Two resultant protein products of the JADE1 gene were designated JADE1S for the short (which is same as(3)) and JADE1L for the long isoform. Several minor transcripts are also detected. The database analysis revealed two additional JADE1 paralogues and members of JADE family, JADE2, and JADE3. JADE3 is identical to E9 protein identified in an earlier independent study which suggested role in apoptosis for PHF16/JADE3/E9 in breast cancer cells.[8]
JADE1 has been mapped to chromosome 4 (4q26-q27). JADE1 is conserved and its orthologues have been found or predicted in most every metazoan. Gene structure and sequences, variants, conservation, orthologues and paralogs, JADE1 phylogenetic tree and large scale screening of JADE1 tissue expression can be found in several extensive databases (https://www.genecards.org; http://useast.ensembl.org).
# Structure
The full length JADE1 polypeptide bears one canonical and one extended PHD zinc finger domains.[9] Other domains include the N-terminal candidate PEST domain, Enhancer of polycomb-like domain and the C-terminal nuclear localization (NLS) signal[2][7] (prosite.expasy.org). JADE1 protein is a target for post translational modifications, including phosphorylation (Fig 1
). Six amino acid residues were identified to be phosphorylated in cell cycle-dependent manner via Aurora A kinase pathway.[10][11] JADE1 is a target of phosphorylation by Casein kinase 2 (CK2).[12] In addition, multiple phosphorylation sites are found by high throughput screening approaches and in silico analysis. Summary schematic for JADE1L and JADE1S proteins phosphorylation sites with references are found in.[11]
Proteins bearing in tandem canonical and extended PHD fingers form a small subfamily within the large PHD protein family (www.genenames.org). Other proteins bearing tandem of PHD fingers and related to JADE1 include proteins that are components of chromatin binding and modifying complexes BRPF1, BRPF3, BRD1.[13] The crystal structure of JADE1 PHD domains has not been solved. Canonical PHD finger motif has signature C4HC3, represents relatively small, stable structure, and is distinct from the C3HC4 type RING finger. PHD domains are able to recognize and bind specific methylated lysine of histone H3, which defined these domains as epigenetic histone code readers.[14][15][16] Reviews describing structure and properties of PHD fingers in depth are available.[17][18][19][20]
# Cellular function
JADE1 proteins are multifunctional and interact with several protein partners.
## Histone acetylation
Function of JADE1 in histone acetylation and transcription activation which required the second extended PHD zinc finger was reported in 2004(16). JADE1 dramatically increases levels of acetylated histone H4 within chromatin, but not histone H3, a specificity characteristic to the MYST family HAT TIP60 and HBO1. TIP60 physically associates with JADE1 and augments JADE1 HAT function in live cells. TIP60 and JADE1 mutually stabilized each other. Transcriptional and HAT activities of JADE1 require PHD2. Results suggest the chromatin targeting role for JADE1 PHD2.[21] In addition, PHD2 of JADE1 binds the N-terminal tail of histone H3 within chromatin context irrespective of methylation status.[22]
Studies analyzing native complexes of INhibitor of Growth (ING) PHD finger family of proteins revealed that ING4 and ING5 proteins are associated with JADE1S and HAT HBO1,[23] while ING3 is associated with EPC1 (JADE1 homolog), TIP60 (HBO1 homolog) and several other partners. Both complexes also included a small Eaf6 protein. The biochemical and in silico analysis of complexes formed by HBO1 and TIP60 suggested common architecture and supported the role for JADE1 in bulk histone H4 acetylation. Characterization of JADE1 and HBO1 functional interactions show structural and functional similarities between the complexes(16, 19). Similarly to TIP60, JADE1 and HBO1 mutually stabilize each other.[24] JADE1 binds to and enables HBO1 to enhance global histone H4 acetylation, which requires intact PHD2 finger.[24]
Similarly to HBO1, JADE1 is responsible for bulk histone H4 acetylation in cultured cells. H4K5, H4K12, and most likely H4K8 are targets of JADE1-dependent acetylation in cultured cells and in vivo.[10][22][25]
Several potential transcription targets of JADE1 have been suggested from experiments using screening approaches.[22][26] According to screening genomic analysis done by ChIP-chip assay JADE1L complex is found mainly along the coding regions of many genes and JADE1L abundance correlates mostly with H3K36me3 histone mark. JADE1L over expression correlates with increased quantities of H4acK8 in the coding region of many genes.[22] The two PHD zinc fingers of JADE1 appear to bind preferentially non-methylated N-terminal peptide of histone.[22][26][27]
JADE1 isoforms assemble at least two different complexes, JADE1L-HBO1-ING4/5 and JADE1S-HBO1 complex.[24] Due to the lack of the C-terminal fragment, JADE1S is incapable of binding ING4/5 partners.[24] A small less characterized protein Eaf6 is also another component of JADE1 complexes.[26]
## Cell cycle
Acetylation of N-terminal fragments of bulk histone H4 has been known to correlate with DNA synthesis and cell division.[28][29][30][31][32] Several studies support cell cycle role for JADE1 linked to HBO1 pathway.[21][25] Both, JADE1 and HBO1 are independently required for the acetylation of bulk histone H4 in cultured cells.[21][23][24][25] The depletion of JADE1 proteins by siRNA results in 1) decreased levels of histone H4 bulk acetylation; 2) slower rates of DNA synthesis in cultured cells;[25] 3) decreased levels of the total and chromatin-bound HBO1;[24][25] 4) abrogation of chromatin recruitment of MCM7.[25] Agreeing with these results, JADE1L over-expression increases chromatin-bound MCM3 protein.[33] The effects of JADE1 depletion on DNA replication events are similar to those described originally for HBO1[34] and suggests adaptor role for JADE1 in HBO1-mediated cell cycle regulation.
JADE1 role in DNA damage has been suggested. A recently discovered non-coding RNA lncRNA-JADE regulates JADE1 expression and provides a functional link between the DNA damage response (DDR) and bulk histone H4 acetylation.[35] Results support role in DNA synthesis linked to histone H4 acetylation.[35] In cultured cells knock down of lncRNA-JADE increased cells sensitivity to DNA damaging drugs. In mice tumor xenograft model, the knock down of lncRNA-JADE inhibited xenograft mammary tumor growth. In a pilot human study, higher levels of lncRNA-JADE as well as JADE1 protein were detected in breast cancer tissues compared to normal tissues. Lastly, the higher levels of JADE1 protein inversely correlated with survival rates of patients with breast cancer. The study suggests that lncRNA-JADE might contribute to breast tumorigenesis, and that JADE1 protein mediates at least part of this effect.[35]
JADE1 and cytokinesis. JADE1S negatively regulates cytokinesis of the epithelial cell cycle, a function specific to the small isoform.[10][11] First report that suggested JADE1 function in G2/M/G1 transition showed that during the late G2 phase, JADE1S undergoes phosphorylation linked to its dissociation from chromatin into the cytoplasm. Mass Spectral analysis identified that total of six individual amino acid residues are phosphorylated by a mitotic kinase.[10] Based on pharmacological analysis, JADE1 phosphorylation and compartmentalization is regulated by Aurora A and Aurora B pathways.[10][11] Other kinases have been reported and may play a role.[12][36] Upon completion of mitosis around telophase, the main pool of the JADE1S protein undergoes de-phosphorylation and re-associates with apparently condensing chromatin inside the reformed nuclei.[10] A discrete pool of JADE1S associates with the cleavage furrow and subsequently appears in the midbody of the cytokinetic bridge.[11] Only JADE1S, but not JADE1L or HBO1 was found in the midbody of the cells undergoing cytokinesis. The spatial regulation of JADE1S during the cell division suggested role in G2/M to G1 transition, which includes cytokinesis and final abscission.[11][37]
Cytokinesis is the final step of cell cycle which controls fidelity of division of cellular content, including cytoplasm, membrane, and chromatin. Cytokinetic bridge is severed during the final abscission which occurs near the midbody and may take up to 2 hours. Cytokinesis and final abscission are tightly controlled by regulatory protein complexes and checkpoint proteins. The number of reports concerning cytokinesis control has been growing over the past decade.[38][39][40][41][42]
JADE1 role in cytokinesis was demonstrated by use of several functional assays and cell culture models.[11] DNA profiling by FACS showed that JADE1S depletion facilitated rates of G1-cells accumulation in synchronously dividing HeLa cells. The depletion of JADE1S protein in asynchronously dividing cells decreased the proportion of cytokinetic cells, and increased the proportion of multi-nuclear cells. The data demonstrated that JADE1 negatively controls cytokinesis, presumably by contributing to cytokinesis delay. JADE1 down-regulation increased number of multi-nuclear cells indicative of failed cytokinesis, while JADE1S moderate overexpression augmented the number of cytokinetic cells indicative of cytokinetic delay. Inhibition of Aurora B kinase by specific small molecule drugs resulted in the release of JADE1S-mediated cytokinetic delay and allowed progression of abscission. Since Aurora B is a key regulator of the NoCut, JADE1S is likely to regulate cytokinesis at the abscission checkpoint control.[11][37]
JADE1S but not JADE1L or HBO1 was found in centrosomes of dividing cells throughout the cell cycle, and neither of these proteins was found in cilia. In contrast, another study reported JADE1 localization to the cilia and centrosome.[36] The study did not communicate on JADE1 isoform specificity.[36] Centrosomes are the cytoskeleton nucleation centers. Centrosome signaling contributes to the definition of cell shape, motility, orientation, polarity, division plane and to the fidelity of sister chromosome separation during mitosis and cytokinesis.[43][44]
## pVHL
The first protein partner of JADE1S has been identified in 2002 in a study searching for new partners of the pVHL, which is a tumor suppressor.[7] A few follow up studies characterized binding and provided some insights on functional interactions of JADE1-pVHL.[45][46][47]
The human pVHL is mutated in von Hippel–Lindau hereditary disease, and in majority of sporadic clear cell renal carcinomas.[48][49][50][51][52] Properties and function of pVHL have been investigated for many decades and extensive literature is available. One of the better known functions of pVHL is to mediate protein ubiquitination and proteosomal degradation. As a component of ubiquitin ligase E3 complex pVHL binds and targets several known factors, including HIF1a and HIF2a for ubiquitination.[51] Mechanism of HIF1a activation by hypoxia and role of pVHL in this pathway has been reported over a decade ago.[53] The VHL protein has been intensely studied and the link of naturally occurring mutations to cancers established. Other causative HIF-1a-independent pVHL pathways have been considered.[54] The pVHL-JADE1S physical interaction was identified by yeast-two hybrid screening analysis and was further confirmed biochemically. Co-transfection of pVHL increased JADE1S protein half-life and abundance, suggesting potential positive relationship.[7] Certain pVHL cancer-derived truncations but not point mutations diminished pVHL-JADE1 stabilization function, suggesting link to pVHL-associated cancers.[47]
Molecular pathways and cellular significance of JADE1-pVHL interactions are not well understood. Single study describing JADE1S intrinsic ubiquitin-ligase activity and ubiquitination of beta-catenin has been reported in year 2008.[45] Based on that study a model has been proposed that pVHL regulates beta-catenin through JADE1, and PHD zinc fingers are required for this activity.
## Apoptosis
JADE1S function in apoptosis has been proposed but the mechanisms remain elusive and results are hard to reconcile.[7][26][45][46][47] According to studies, JADE1 overexpression slows rates of cellular growth and induces cell cycle arrest protein p21. Several attempts to establish dependable cell lines stably expressing JADE1S protein have not been successful, presumably due to the negative cells self-selection. Contrary to that, another study shows that JADE1 downregulation decreased rates of DNA synthesis in synchronously dividing cells.[24][35] According to indirect immunofluorescence and microscopy analysis of cultured cells, cultured cells overload with JADE1 protein causes cell toxicity and side effects.[11] Cells undergo morphological changes that do not resemble apoptosis but suggest severely impaired cell cycle including dyeing cells with abnormal shapes and large, multi-lobular nuclei.[11] Based on JADE1S-mediated regulation of cell cycle other interpretations are considered: JADE1 overload might cause prolonged NoCut and stalled cytokinesis or severe cell cycle misbalance rather than direct transcription activation of apoptosis.[11]
# Biological role
The biological role of JADE1 has not been elucidated. Limited number of publications addresses this question using mice models. The most comprehensive study which was published in 2003, identified mice orthologue of human JADE1, Jade1, and investigated Jade1 expression during mice embryogenesis.[2] Searching for developmentally regulated genes the authors used gene trap screen analysis and identified mouse Jade1 as gene strongly regulated during embryogenesis. Insertion of the vector into the third intron of the Jade1 gene lead to the production of a 47-amino-acid truncated protein. The gene trap insertional mutation resulted in Jade1-beta-galactosidase reporter fusion product and Jade1 null allele. While the homozygotes for the gene trap integration did not produce strong developmental phenotype, the fusion product revealed Jade1 gene spatial-temporal expression in mouse embryonic cells and tissues of developing embryo up to 15.5-d.p.c. In addition the study reports experimental and in silico comparative analysis of Jade1 mRNA transcripts, Jade1 gene structure and analysis of Jade1 protein orthologues from mouse human and zebra fish.[2]
Jade1 expression was detected in extraembryonic ectoderm and trophoblast, which are placental components important for vasculogenesis, as well as in sites enriched with multipotent or tissue-specific progenitors, including neural progenitors(2). The dynamics of Jade1 reporter expression in these areas indicates the involvement in the determination and elongation of anterior posterior axis, an important point of the study).[2] The potential role for human JADE1 in the renewal of embryonic stem cell and embryonal carcinoma cell cultures was suggested in another screening study which showed that, in cultured stem cells activation of stem cell transcription factor OCT4 pathway upregulated JADE1 gene expression along with stem cell factors NANOG, PHC1, USP44 and SOX2.[55]
Role of JADE1 in epithelial cell proliferation was addressed in a murine model of acute kidney injury and regeneration.[10][25] Expression patterns and dynamics of HBO1-JADE1S/L were examined in regenerating tubular epithelial cells.[25] Ischemia and reperfusion injury resulted in an initial decrease in JADE1S, JADE1L, and HBO1 protein levels, which returned to the baseline during renal recovery. Expression levels of HBO1 and JADE1S recovered as cell proliferation rate reached maximum, whereas JADE1L recovered after bulk proliferation had diminished. The temporal expression of JADE1 correlated with the acetylation of histone H4 (H4K5 and H4K12) but not that of histone H3 (H4K14), suggesting that the JADE1-HBO1 complex specifically marks H4 during epithelial cell proliferation. The results of the study implicate JADE1-HBO1 complex in acute kidney injury and suggest distinct roles for JADE1 isoforms during epithelial cell recovery.[25]
# Disease associations
Role of JADE1 in human disease has not been elucidated. A recent study searched for novel submicroscopic genetic changes in myelofibrosis, which is a bone marrow cancer.[56] The study identified seven novel deletions and translocations in small cohort of patients with primary myelofibrosis. JADE1 and the adjacent gene called Sodium channel and clathrin linker 1 (SCLT1) were significantly modified. As a result of mutation, JADE1 gene has deletions of intron 5-6 and exons 6-11, which would produce JADE1 missing a large chunk of protein starting from the PHD zinc finger. The relevance to pathogenesis is under investigation.
In a handful of pilot studies JADE1 expression was examined in colon cancers and renal carcinomas. The results in these studies do not always reconcile. The results of some studies are generated mostly from the histochemical analysis of tumor specimens using JADE1 antibody with uncharacterized specificities towards JADE1 in general, and JADE1S or JADE1L in particular.[57][58] Results of study using in silico microarray algorithm analysis shows, that PHF17 mRNA may play a role in the development of pancreatic cancer.[59] These promising lines of investigations require further controls and additional assessments.
# Interactions
Several proteins interact with JADE1, including: pVHL,[7] TIP60,[21] HBO1, ING4, ING5,[24] ß-catenin,[45] NPHP4.[36]
# Notes | https://www.wikidoc.org/index.php/JADE1 | |
85c6701b745de1d4843ce58aa91c0b0bef091bdb | wikidoc | Joule | Joule
The joule (Template:PronEng or Template:IPA) (symbol: J) is the SI unit of energy. It was named after James Prescott Joule for his work on the relationship between heat, electricity and mechanical work.
# Description
One joule is the work done, or energy expended, by a force of one newton moving one meter along the direction of the force. This quantity is also denoted as a newton-meter with the symbol N·m. Note that torque also has the same units as work, but the quantities are not identical. In elementary units:
One joule is also:
- The work required to move an electric charge of one coulomb through an electrical potential difference of one volt; or one coulomb volt, with the symbol C·V.
- The work done to produce power of one watt continuously for one second; or one watt second (compare kilowatt-hour), with the symbol W·s. Thus a kilowatt-hour is 3,600,000 joules or 3.6 megajoules
# History
A joule is the mechanical equivalent of heat meaning the number of units of work in which the unit of heat can perform.. Its value was found by James Prescott Joule in experiments that showed the mechanical energy Joule's equivalent, and represented by the symbol J. The term was first introduced by Dr. Mayer of Heilbronn.
# Conversions
1 joule is exactly 107 ergs.
1 joule is approximately equal to:
- 6.24150636309 Template:E eV (electronvolts)
- 0.238845896628 cal (calorie) (small calories, lower case c)
- 2.390 Template:E kilocalorie, Calories (food energy, upper case C)
- 9.47817120313 Template:E BTU (British thermal unit)
- 0.737562149277 ft·lbf (foot-pound force)
- 23.7 ft·pdl (foot poundals)
- 2.7778 Template:E kilowatt-hour
- 2.7778 Template:E watt-hour
- 9.8692 Template:E litre-atmosphere
Units defined in terms of the joule include:
- 1 thermochemical calorie = 4.184 J
- 1 International Table calorie = 4.1868 J
- 1 watt-hour = 3600 J
- 1 kilowatt-hour = 3.6 Template:E J (or 3.6 MJ)
Useful to remember:
- 1 joule = 1 newton-metre = 1 watt-second
1 joule in everyday life is approximately:
- the energy required to lift a small apple one meter straight up.
- the energy released when that same apple falls one meter to the ground.
- the amount of energy, as heat, that a quiet person produces every hundredth of a second.
- the energy required to heat one gram of dry, cool air by 1 degree Celsius.
- one hundredth of the energy a person can get by drinking a single drop of beer.
## SI multiples | Joule
The joule (Template:PronEng or Template:IPA) (symbol: J) is the SI unit of energy. It was named after James Prescott Joule for his work on the relationship between heat, electricity and mechanical work.
# Description
One joule is the work done, or energy expended, by a force of one newton moving one meter along the direction of the force. This quantity is also denoted as a newton-meter with the symbol N·m. Note that torque also has the same units as work, but the quantities are not identical. In elementary units:
One joule is also:
- The work required to move an electric charge of one coulomb through an electrical potential difference of one volt; or one coulomb volt, with the symbol C·V.
- The work done to produce power of one watt continuously for one second; or one watt second (compare kilowatt-hour), with the symbol W·s. Thus a kilowatt-hour is 3,600,000 joules or 3.6 megajoules
# History
A joule is the mechanical equivalent of heat meaning the number of units of work in which the unit of heat can perform.. Its value was found by James Prescott Joule in experiments that showed the mechanical energy Joule's equivalent, and represented by the symbol J. The term was first introduced by Dr. Mayer of Heilbronn.
# Conversions
1 joule is exactly 107 ergs.
1 joule is approximately equal to:
- 6.24150636309 Template:E eV (electronvolts)
- 0.238845896628 cal (calorie) (small calories, lower case c)
- 2.390 Template:E kilocalorie, Calories (food energy, upper case C)
- 9.47817120313 Template:E BTU (British thermal unit)
- 0.737562149277 ft·lbf (foot-pound force)
- 23.7 ft·pdl (foot poundals)
- 2.7778 Template:E kilowatt-hour
- 2.7778 Template:E watt-hour
- 9.8692 Template:E litre-atmosphere
Units defined in terms of the joule include:
- 1 thermochemical calorie = 4.184 J
- 1 International Table calorie = 4.1868 J
- 1 watt-hour = 3600 J
- 1 kilowatt-hour = 3.6 Template:E J (or 3.6 MJ)
Useful to remember:
- 1 joule = 1 newton-metre = 1 watt-second
1 joule in everyday life is approximately:
- the energy required to lift a small apple one meter straight up.
- the energy released when that same apple falls one meter to the ground.
- the amount of energy, as heat, that a quiet person produces every hundredth of a second.
- the energy required to heat one gram of dry, cool air by 1 degree Celsius.
- one hundredth of the energy a person can get by drinking a single drop of beer.
## SI multiples
Template:SI multiples
Template:SI unit lowercase | https://www.wikidoc.org/index.php/Joule | |
420d39a3c266b41013f20a0616f993d9c7338301 | wikidoc | Juice | Juice
Juice is a liquid naturally contained in fruit or vegetable tissue. Juice is prepared by mechanically squeezing or macerating fresh fruits or vegetables without the application of heat or solvents. For example, orange juice is the liquid extract of the fruit of the orange tree. Juice may be prepared in the home from fresh fruits and vegetables using variety of hand or electric juicers. Many commercial juices are filtered to remove fiber or pulp, but high pulp fresh orange juice is marketed as an alternative. Juice may be marketed in concentrate form, sometimes frozen, requiring the user to add water to reconstitute the liquid back to its "original state". (Generally, concentrates have a noticeably different taste than their comparable "fresh-squeezed" versions). Other juices are reconstituted before packaging for retail sale. Common methods for preservation and processing of fruit juices include canning, pasteurization, freezing, evaporation and spray drying.
# Varieties
Popular juices include but are not limited to apple, orange, grapefruit, pineapple, tomato, mango, carrot, grape, cranberry and pomegranate. It has become increasingly popular to combine a variety of fruits into single juice drinks. Popular blends include cran-apple (cranberry and apple) and apple and blackcurrant. Prepackaged single fruit juices have lost market share to prepackaged fruit juice combinations. A number of new companies have had considerable success supplying prepackaged fruit juice combinations on the basis of this transition. "Innocent" and "P&J" are UK examples; "Nudie" is an Australian example.
Juice bars have also become commonplace across most of the western world and offer similar juices. Most of these juice bars offer freshly made fruit juices and claim that that confers greater health benefit. The rationale for this claim is that once the fruit has been juiced, its antioxidants start to react with oxygen free radicals and so lose their health benefit. Juice is also commonly found in many cooking recipes around the world. The most popular are lime and lemon juice which help to add a slightly more sour or bitter taste to dishes.
# Labeling
Juice normally has a standard defined level of purity, which is 100% in many countries.
In the UK, the term fruit juice can only legally be used to describe a product which is 100% fruit juice, as required by the Fruit Juices and Fruit Nectars (England) Regulations and The Fruit Juices & Fruit Nectars (Scotland) Regulations 2003. However, the term "juice drink" can be used to describe any drink which includes juice, even if the juice content is 1% of the overall volume.
In the USA, fruit juice can only legally be used to describe a product which is 100% fruit juice. A blend of fruit juice(s) with other ingredients, such as high-fructose corn syrup, is called a juice cocktail or juice drink According to the FDA, the term "nectar" is generally accepted in the U.S. and in international trade for a diluted juice to denote a beverage that contains fruit juice or puree, water, and which may contain sweeteners.
In New Zealand (and possibly others), juice denotes a sweetened fruit extract, whereas nectar denotes a pure fruit or vegetable extract.
However, fruit juice labels may be misleading, with juice companies actively hiding the actual content. "No added sugar" is commonly placed on labels, but the products are often made from "reconstituted concentrates" which function similarly to sugars and other, the naturally occurring fructose is still unhealthy for the consumer. It is difficult for the consumer to know the contents of the concentrates.
Juice does not contain a carbonated beverage, but some carbonated beverages, such as Orangina, are sold with actual fruit juice as an ingredient.
# Health benefits
Juices are often consumed for their health benefits. For example, orange juice is rich in vitamin C, while prune juice is associated with a digestive health benefit. Cranberry juice has long been known to help prevent or even treat bladder infections, and it is now known that a substance in cranberries prevents bacteria from binding to the bladder.
Fruit juice consumption overall in Europe, Australia, New Zealand and the USA has increased in recent years, probably due to public perception of juices as a healthy natural source of nutrients and increased public interest in health issues.
The perception of fruit juice as equal in health benefit to consumption of fresh fruit has been questioned due mainly to the lack of fiber and the processing they endure. The high amounts of fructose in fruit juice when not consumed with fiber, have been suggested as a contributor to the growing diabetes epidemic in the West. High-fructose corn syrup, an ingredient of many juice cocktails, has also been linked to the increased incidence of type II diabetes. The high consumption of juice is also linked to people putting on extra weight. | Juice
Juice is a liquid naturally contained in fruit or vegetable tissue. Juice is prepared by mechanically squeezing or macerating fresh fruits or vegetables without the application of heat or solvents. For example, orange juice is the liquid extract of the fruit of the orange tree. Juice may be prepared in the home from fresh fruits and vegetables using variety of hand or electric juicers. Many commercial juices are filtered to remove fiber or pulp, but high pulp fresh orange juice is marketed as an alternative. Juice may be marketed in concentrate form, sometimes frozen, requiring the user to add water to reconstitute the liquid back to its "original state". (Generally, concentrates have a noticeably different taste than their comparable "fresh-squeezed" versions). Other juices are reconstituted before packaging for retail sale. Common methods for preservation and processing of fruit juices include canning, pasteurization, freezing, evaporation and spray drying.
# Varieties
Popular juices include but are not limited to apple, orange, grapefruit, pineapple, tomato, mango, carrot, grape, cranberry and pomegranate. It has become increasingly popular to combine a variety of fruits into single juice drinks. Popular blends include cran-apple (cranberry and apple) and apple and blackcurrant. Prepackaged single fruit juices have lost market share to prepackaged fruit juice combinations. A number of new companies have had considerable success supplying prepackaged fruit juice combinations on the basis of this transition. "Innocent" and "P&J" are UK examples; "Nudie" is an Australian example.
Juice bars have also become commonplace across most of the western world and offer similar juices. Most of these juice bars offer freshly made fruit juices and claim that that confers greater health benefit. The rationale for this claim is that once the fruit has been juiced, its antioxidants start to react with oxygen free radicals and so lose their health benefit.[citation needed] Juice is also commonly found in many cooking recipes around the world. The most popular are lime and lemon juice which help to add a slightly more sour or bitter taste to dishes.
# Labeling
Juice normally has a standard defined level of purity, which is 100% in many countries.
In the UK, the term fruit juice can only legally be used to describe a product which is 100% fruit juice, as required by the Fruit Juices and Fruit Nectars (England) Regulations[1] and The Fruit Juices & Fruit Nectars (Scotland) Regulations 2003.[2] However, the term "juice drink" can be used to describe any drink which includes juice, even if the juice content is 1% of the overall volume.[3]
In the USA, fruit juice can only legally be used to describe a product which is 100% fruit juice. A blend of fruit juice(s) with other ingredients, such as high-fructose corn syrup, is called a juice cocktail or juice drink[4] According to the FDA, the term "nectar" is generally accepted in the U.S. and in international trade for a diluted juice to denote a beverage that contains fruit juice or puree, water, and which may contain sweeteners.[5]
In New Zealand (and possibly others), juice denotes a sweetened fruit extract, whereas nectar denotes a pure fruit or vegetable extract[citation needed].
However, fruit juice labels may be misleading, with juice companies actively hiding the actual content. "No added sugar" is commonly placed on labels, but the products are often made from "reconstituted concentrates" which function similarly to sugars and other, the naturally occurring fructose is still unhealthy for the consumer. It is difficult for the consumer to know the contents of the concentrates[6][7].
Juice does not contain a carbonated beverage, but some carbonated beverages, such as Orangina, are sold with actual fruit juice as an ingredient.
# Health benefits
Juices are often consumed for their health benefits. For example, orange juice is rich in vitamin C, while prune juice is associated with a digestive health benefit. Cranberry juice has long been known to help prevent or even treat bladder infections, and it is now known that a substance in cranberries prevents bacteria from binding to the bladder.[8]
Fruit juice consumption overall in Europe, Australia, New Zealand and the USA has increased in recent years[9], probably due to public perception of juices as a healthy natural source of nutrients and increased public interest in health issues.
The perception of fruit juice as equal in health benefit to consumption of fresh fruit has been questioned due mainly to the lack of fiber and the processing they endure. The high amounts of fructose in fruit juice when not consumed with fiber, have been suggested as a contributor to the growing diabetes epidemic in the West.[citation needed] High-fructose corn syrup, an ingredient of many juice cocktails, has also been linked to the increased incidence of type II diabetes.[10] The high consumption of juice is also linked to people putting on extra weight. [11] | https://www.wikidoc.org/index.php/Juice | |
45d370fb84f83af98cdaed732370cfaf3e51b417 | wikidoc | KCNA2 | KCNA2
Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the KCNA2 gene.
# Function
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1.
# Interactions
KCNA2 has been shown to interact with KCNA4, DLG4, PTPRA, KCNAB2, RHOA and Cortactin.
# Clinical
Mutations in this gene have been associated with hereditary spastic paraplegia. | KCNA2
Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the KCNA2 gene.[1][2]
# Function
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1.[2]
# Interactions
KCNA2 has been shown to interact with KCNA4,[3] DLG4,[4] PTPRA,[5] KCNAB2,[3][6] RHOA[7] and Cortactin.[8]
# Clinical
Mutations in this gene have been associated with hereditary spastic paraplegia.[9] | https://www.wikidoc.org/index.php/KCNA2 | |
3494af42f13608aa3fe5e5c3eeccf90b9764438c | wikidoc | KCNA3 | KCNA3
Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein that in humans is encoded by the KCNA3 gene.
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes – shaker, shaw, shab, and shal – have been identified in Drosophila, and each has been shown to have human homolog(s).
This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. It plays an essential role in T cell proliferation and activation. This gene appears to be intronless and is clustered together with KCNA2 and KCNA10 genes on chromosome 1.
# Function
KCNA3 encodes the voltage-gated Kv1.3 channel, which is expressed in T and B lymphocytes. All human T cells express roughly 300 Kv1.3 channels per cell along with 10-20 calcium-activated KCa3.1 channels. Upon activation, naive and central memory T cells increase expression of the KCa3.1 channel to approximately 500 channels per cell, while effector-memory T cells increase expression of the Kv1.3 channel. Among human B cells, naive and early memory B cells express small numbers of Kv1.3 and KCa3.1 channels when they are quiescent, and augment KCa3.1 expression after activation. In contrast, class-switched memory B cells express high numbers of Kv1.3 channels per cell (about 1500/cell) and this number increases after activation.
Kv1.3 is physically coupled through a series of adaptor proteins to the T-cell receptor signaling complex and it traffics to the immunological synapse during antigen presentation. However, blockade of the channel does not prevent immune synapse formation. Kv1.3 and KCa3.1 regulate membrane potential and calcium signaling of T cells. Calcium entry through the CRAC channel is promoted by potassium efflux through the Kv1.3 and KCa3.1 potassium channels.
Blockade of Kv1.3 channels in effector-memory T cells suppresses calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation. In vivo, Kv1.3 blockers paralyze effector-memory T cells at the sites of inflammation and prevent their reactivation in inflamed tissues. In contrast, Kv1.3 blockers do not affect the homing to and motility within lymph nodes of naive and central memory T cells, most likely because these cells express the KCa3.1 channel and are, therefore, protected from the effect of Kv1.3 blockade.
Kv1.3 has been reported to be expressed in the inner mitochondrial membrane in lymphocytes. The apoptotic protein Bax has been suggested to insert into the outer mitochondrial membrane and occlude the pore of Kv1.3 via a lysine residue. Thus, Kv1.3 modulation may be one of many mechanisms that contribute to apoptosis.
# Clinical significance
## Autoimmune
In patients with multiple sclerosis (MS), disease-associated myelin-specific T cells from the blood are predominantly co-stimulation-independent effector-memory T cells that express high numbers of Kv1.3 channels. T cells in MS lesions in postmortem brain lesions are also predominantly effector-memory T cells that express high levels of the Kv1.3 channel. In children with type-1 diabetes mellitus, the disease-associated insulin- and GAD65-specific T cells isolated from the blood are effector-memory T cells that express high numbers of Kv1.3 channels, and the same is true of T cells from the synovial joint fluid of patients with rheumatoid arthritis. T cells with other antigen specificities in these patients were naive or central memory T cells that upregulate the KCa3.1 channel upon activation. Consequently, it should be possible to selectively suppress effector-memory T cells with a Kv1.3-specific blocker and thereby ameliorate many autoimmune diseases without compromising the protective immune response. In proof-of-concept studies, Kv1.3 blockers have prevented and treated disease in rat models of multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, contact dermatitis, and delayed-type hypersensitivity.
At therapeutic concentrations, the blockers did not cause any clinically evident toxicity in rodents, and it did not compromise the protective immune response to acute influenza viral infection and acute chlamydia bacterial infection. Many groups are developing Kv1.3 blockers for the treatment of autoimmune diseases.
## Metabolic
Kv1.3 is also considered a therapeutic target for the treatment of obesity, for enhancing peripheral insulin sensitivity in patients with type-2 diabetes mellitus, and for preventing bone resorption in periodontal disease. A genetic variation in the Kv1.3 promoter region is associated with low insulin sensitivity and impaired glucose tolerance.
## Neurodegeneration
Kv1.3 channels have been found to be highly expressed by activated and plaque-associated microglia in human Alzheimer’s disease (AD) post-mortem brains as well as in mouse models of AD pathology. Patch-clamp recordings and flow cytometric studies performed on acutely isolated mouse microglia have confirmed upregulation of Kv1.3 channels with disease progression in mouse AD models. The Kv1.3 channel gene has also been found to be a regulator of pro-inflammatory microglial responses. Selective blockade of Kv1.3 channels by the small molecule Pap1 as well as a peptide sea anemone toxin-based peptide ShK-223 have been found to limit amyloid beta plaque burden in mouse AD models, potentially via augmented clearance by microglia.
# Blockers
Kv1.3 is blocked by several peptides from venomous creatures including scorpions (ADWX1, OSK1, margatoxin, kaliotoxin, charybdotoxin, noxiustoxin, anuroctoxin) and sea anemone (ShK, ShK-F6CA, ShK-186, ShK-192, BgK), and by small molecule compounds (e.g., PAP-1, Psora-4, correolide, benzamides, CP339818, progesterone and the anti-lepromatous drug clofazimine). The Kv1.3 blocker clofazimine has been reported to be effective in the treatment of chronic graft-versus-host disease, cutaneous lupus, and pustular psoriasis in humans. Furthermore, clofazimine in combination with the antibiotics clarithromycin and rifabutin induced remission for about 2 years in patients with Crohn's disease, but the effect was temporary; the effect was thought to be due to anti-mycobacterial activity, but could well have been an immunomodulatory effect by clofazimine. | KCNA3
Potassium voltage-gated channel, shaker-related subfamily, member 3, also known as KCNA3 or Kv1.3, is a protein that in humans is encoded by the KCNA3 gene.[1][2][3]
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes – shaker, shaw, shab, and shal – have been identified in Drosophila, and each has been shown to have human homolog(s).
This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. It plays an essential role in T cell proliferation and activation. This gene appears to be intronless and is clustered together with KCNA2 and KCNA10 genes on chromosome 1.[1]
# Function
KCNA3 encodes the voltage-gated Kv1.3 channel, which is expressed in T and B lymphocytes.[2][4][5][6][7][8][9] All human T cells express roughly 300 Kv1.3 channels per cell along with 10-20 calcium-activated KCa3.1 channels.[10][11] Upon activation, naive and central memory T cells increase expression of the KCa3.1 channel to approximately 500 channels per cell, while effector-memory T cells increase expression of the Kv1.3 channel.[10][11] Among human B cells, naive and early memory B cells express small numbers of Kv1.3 and KCa3.1 channels when they are quiescent, and augment KCa3.1 expression after activation.[12] In contrast, class-switched memory B cells express high numbers of Kv1.3 channels per cell (about 1500/cell) and this number increases after activation.[12]
Kv1.3 is physically coupled through a series of adaptor proteins to the T-cell receptor signaling complex and it traffics to the immunological synapse during antigen presentation.[13][14] However, blockade of the channel does not prevent immune synapse formation.[14] Kv1.3 and KCa3.1 regulate membrane potential and calcium signaling of T cells.[10] Calcium entry through the CRAC channel is promoted by potassium efflux through the Kv1.3 and KCa3.1 potassium channels.[14][15]
Blockade of Kv1.3 channels in effector-memory T cells suppresses calcium signaling, cytokine production (interferon-gamma, interleukin 2) and cell proliferation.[10][11][14] In vivo, Kv1.3 blockers paralyze effector-memory T cells at the sites of inflammation and prevent their reactivation in inflamed tissues.[15] In contrast, Kv1.3 blockers do not affect the homing to and motility within lymph nodes of naive and central memory T cells, most likely because these cells express the KCa3.1 channel and are, therefore, protected from the effect of Kv1.3 blockade.[15]
Kv1.3 has been reported to be expressed in the inner mitochondrial membrane in lymphocytes.[16] The apoptotic protein Bax has been suggested to insert into the outer mitochondrial membrane and occlude the pore of Kv1.3 via a lysine residue.[17] Thus, Kv1.3 modulation may be one of many mechanisms that contribute to apoptosis.[16][17][18][19][20]
# Clinical significance
## Autoimmune
In patients with multiple sclerosis (MS), disease-associated myelin-specific T cells from the blood are predominantly co-stimulation-independent[21] effector-memory T cells that express high numbers of Kv1.3 channels.[11][14] T cells in MS lesions in postmortem brain lesions are also predominantly effector-memory T cells that express high levels of the Kv1.3 channel.[22] In children with type-1 diabetes mellitus, the disease-associated insulin- and GAD65-specific T cells isolated from the blood are effector-memory T cells that express high numbers of Kv1.3 channels, and the same is true of T cells from the synovial joint fluid of patients with rheumatoid arthritis.[14] T cells with other antigen specificities in these patients were naive or central memory T cells that upregulate the KCa3.1 channel upon activation.[14] Consequently, it should be possible to selectively suppress effector-memory T cells with a Kv1.3-specific blocker and thereby ameliorate many autoimmune diseases without compromising the protective immune response. In proof-of-concept studies, Kv1.3 blockers have prevented and treated disease in rat models of multiple sclerosis, type-1 diabetes mellitus, rheumatoid arthritis, contact dermatitis, and delayed-type hypersensitivity.[14][23][24][25][26]
At therapeutic concentrations, the blockers did not cause any clinically evident toxicity in rodents,[14][23] and it did not compromise the protective immune response to acute influenza viral infection and acute chlamydia bacterial infection.[15] Many groups are developing Kv1.3 blockers for the treatment of autoimmune diseases.[27]
## Metabolic
Kv1.3 is also considered a therapeutic target for the treatment of obesity,[28][29] for enhancing peripheral insulin sensitivity in patients with type-2 diabetes mellitus,[30] and for preventing bone resorption in periodontal disease.[31] A genetic variation in the Kv1.3 promoter region is associated with low insulin sensitivity and impaired glucose tolerance.[32]
## Neurodegeneration
Kv1.3 channels have been found to be highly expressed by activated and plaque-associated microglia in human Alzheimer’s disease (AD) post-mortem brains [33] as well as in mouse models of AD pathology.[34] Patch-clamp recordings and flow cytometric studies performed on acutely isolated mouse microglia have confirmed upregulation of Kv1.3 channels with disease progression in mouse AD models.[34][35] The Kv1.3 channel gene has also been found to be a regulator of pro-inflammatory microglial responses.[36] Selective blockade of Kv1.3 channels by the small molecule Pap1 as well as a peptide sea anemone toxin-based peptide ShK-223 have been found to limit amyloid beta plaque burden in mouse AD models, potentially via augmented clearance by microglia.[34][35]
# Blockers
Kv1.3 is blocked[31] by several peptides from venomous creatures including scorpions (ADWX1, OSK1,[37] margatoxin,[38] kaliotoxin, charybdotoxin, noxiustoxin, anuroctoxin)[39][40] and sea anemone (ShK,[41][42][43][44][45] ShK-F6CA, ShK-186, ShK-192,[46] BgK[47]), and by small molecule compounds (e.g., PAP-1,[48] Psora-4,[49] correolide,[50] benzamides,[51] CP339818,[52] progesterone[53] and the anti-lepromatous drug clofazimine[54]). The Kv1.3 blocker clofazimine has been reported to be effective in the treatment of chronic graft-versus-host disease,[55] cutaneous lupus,[56][57] and pustular psoriasis[58][59] in humans. Furthermore, clofazimine in combination with the antibiotics clarithromycin and rifabutin induced remission for about 2 years in patients with Crohn's disease, but the effect was temporary; the effect was thought to be due to anti-mycobacterial activity, but could well have been an immunomodulatory effect by clofazimine.[60] | https://www.wikidoc.org/index.php/KCNA3 | |
8b31c7c2596acf678ddc66716e2392e817653e6b | wikidoc | KCNA4 | KCNA4
Potassium voltage-gated channel subfamily A member 4 also known as Kv1.4 is a protein that in humans is encoded by the KCNA4 gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.
# Description
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the A-type potassium current class, the members of which may be important in the regulation of the fast repolarizing phase of action potentials in heart and thus may influence the duration of cardiac action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1 in humans.
KCNA4 (Kv1.4) contains a tandem inactivation domain at the N terminus. It is composed of two subdomains. Inactivation domain 1 (ID1, residues 1-38) consists of a flexible N terminus anchored at a 5-turn helix, and is thought to work by occluding the ion pathway, as is the case with a classical ball domain. Inactivation domain 2 (ID2, residues 40-50) is a 2.5 turn helix with a high proportion of hydrophobic residues that probably serves to attach ID1 to the cytoplasmic face of the channel. In this way, it can promote rapid access of ID1 to the receptor site in the open channel. ID1 and ID2 function together to bring about fast inactivation of the Kv1.4 channel, which is important for the role of the channel in short-term plasticity.
# Interactions
KCNA4 has been shown to interact with DLG4, KCNA2 and DLG1. | KCNA4
Potassium voltage-gated channel subfamily A member 4 also known as Kv1.4 is a protein that in humans is encoded by the KCNA4 gene.[1][2][3] It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.[4]
# Description
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the A-type potassium current class, the members of which may be important in the regulation of the fast repolarizing phase of action potentials in heart and thus may influence the duration of cardiac action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1 in humans.[3]
KCNA4 (Kv1.4) contains a tandem inactivation domain at the N terminus. It is composed of two subdomains. Inactivation domain 1 (ID1, residues 1-38) consists of a flexible N terminus anchored at a 5-turn helix, and is thought to work by occluding the ion pathway, as is the case with a classical ball domain. Inactivation domain 2 (ID2, residues 40-50) is a 2.5 turn helix with a high proportion of hydrophobic residues that probably serves to attach ID1 to the cytoplasmic face of the channel. In this way, it can promote rapid access of ID1 to the receptor site in the open channel. ID1 and ID2 function together to bring about fast inactivation of the Kv1.4 channel, which is important for the role of the channel in short-term plasticity.[5]
# Interactions
KCNA4 has been shown to interact with DLG4,[6][7][8][9] KCNA2[10] and DLG1.[6][8][11] | https://www.wikidoc.org/index.php/KCNA4 | |
1628007df9952d2f1206be3396ced7032b82b16f | wikidoc | KCNA5 | KCNA5
Potassium voltage-gated channel, shaker-related subfamily, member 5, also known as KCNA5 or Kv1.5, is a protein that in humans is encoded by the KCNA5 gene.
# Function
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. KCNA5 encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, the function of which could restore the resting membrane potential of beta cells after depolarization, thereby contributing to the regulation of insulin secretion. This gene is intronless, and the gene is clustered with genes KCNA1 and KCNA6 on chromosome 12. Mutations in this gene have been related to both atrial fibrillation and sudden cardiac death. KCNA5 are also key players in pulmonary vascular function, where they play a role in setting the resting membrane potential and its involvement during hypoxic pulmonary vasoconstriction.
# Interactions
KCNA5 has been shown to interact with DLG4 and Actinin, alpha 2. | KCNA5
Potassium voltage-gated channel, shaker-related subfamily, member 5, also known as KCNA5 or Kv1.5, is a protein that in humans is encoded by the KCNA5 gene.[1]
# Function
Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. KCNA5 encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, the function of which could restore the resting membrane potential of beta cells after depolarization, thereby contributing to the regulation of insulin secretion. This gene is intronless, and the gene is clustered with genes KCNA1 and KCNA6 on chromosome 12.[1] Mutations in this gene have been related to both atrial fibrillation [2] and sudden cardiac death.[3] KCNA5 are also key players in pulmonary vascular function, where they play a role in setting the resting membrane potential and its involvement during hypoxic pulmonary vasoconstriction.
# Interactions
KCNA5 has been shown to interact with DLG4[4][5] and Actinin, alpha 2.[4][6] | https://www.wikidoc.org/index.php/KCNA5 | |
3bc2d5e2e25785109bd67e1819734b0d943b252c | wikidoc | KCNB1 | KCNB1
Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein that, in humans, is encoded by the KCNB1 gene.
Potassium voltage-gated channel subfamily B member one, or simply known as KCNB1, is a delayed rectifier and voltage-gated potassium channel found throughout the body. The channel has a diverse number of functions. However, its main function, as a delayed rectifier, is to propagate current in its respective location. It is commonly expressed in the central nervous system, but may also be found in pulmonary arteries, auditory outer hair cells, stem cells, the retina, and organs such as the heart and pancreas. Modulation of K+ channel activity and expression has been found to be at the crux of many profound pathophysiological disorders in several cell types.
Potassium channels are among the most diverse of all ion channels in eukaryotes. With over 100 genes coding numerous functions, many isoforms of potassium channels are present in the body, but most are divided up into two main groups: inactivating transient channels and non-inactivating delayed rectifiers. Due to the multiple varied forms, potassium delayed rectifier channels open or close in response to a myriad of signals. These include: cell depolarization or hyperpolarization, increases in intracellular calcium concentrations, neurotransmitter binding, or second messenger activity such as G-proteins or kinases.
# Structure
The general structure of all potassium channels contain a centered pore composed of alpha subunits with a pore loop expressed by a segment of conserved DNA, T/SxxTxGxG. This general sequence comprises the selectivity of the potassium channel. Depending on the channel, the alpha subunits are constructed in either a homo- or hetero-association, creating a 4-subunit selectivity pore or a 2-subunit pore, each with accessory beta subunits attached intracellularly. Also on the cytoplasmic side are the N- and C- termini, which play a crucial role in activating and deactivating KCNB1 channels. This pore creates the main opening of the channel where potassium ions flow through.
The type of pore domain (number of subunits) determines if the channel has the typical 6 transmembrane (protein) spanning regions, or the less dominant inward rectifier type of only 2 regions. KCNB1 has 6TM labeled S1-S6, each with a tetrameric structure. S5 and S6 create the p-loop, while S4 is the location of the voltage sensor. S4, along with S2 and S3 create the ‘activating’ portions of the delayed rectifier channel. The heteromeric complexes that contain the distinct pore are electrically inactive or non-conducting, but unlike other potassium families, the pore of the KCNB1 group has numerous phosphorylation sites allowing kinase activity. Maturing KCNB1 channels develop these phosphorylation sites within the channel pore, but lack a glycosylation stage in the N-terminus.
Specifically, the KCNB1 delayed rectifier channel conducts a potassium current (K+). This mediates high frequency firing due to the phosphorylation sites located within the channel via kinases and a major calcium influx typical of all neurons.
## Kinetics
The kinetics surrounding the activation and deactivation of the KCNB1 channel is relatively unknown, and has been under considerable study. Three of the six transmembrane regions, S2, S3 and S4, contribute to the activation phase of the channel. Upon depolarization, the S4 region, which is positively charged, is moved in response to the subsequent positive charge of the depolarization. As a result of S4 movement, the negatively charged regions of S2 and S3 appear to move as well. The movement of these regions causes an opening of the channel gate within regions of S5 and S6. The intracellular regions of the C and N-terminus also play a crucial role in the activation kinetics of the channel. The two termini interact with one other, as the C-terminus folds around the N-terminus during channel activation. The relative movement between the N- and C- termini greatly aids in producing a conformational change of the channel necessary for channel opening. This interaction between these intracellular regions is believed to be linked with membrane-spanning regions of S1 and S6, and thus aid in the movement of S2, S3, and S4 in opening the channel. Studies on selective mutations knocking out these intracellular termini have been shown to produce larger reductions in speed and probability of channel opening, which indicates their importance in channel activation.
# Function
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Delayed rectifier potassium channels’ most prevalent role is in the falling phase of physiological action potentials. KCNB1 rectifiers are also important in forming the cardiac beat and rate synchronicity that exists within the heart, and the lysis of target molecules in the immune response. These channels can also act as effectors in downstream signaling in G-protein coupled receptor transduction. KCNB1’s regulation and propagation of current provides a means for regulatory control over several physiological functions. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and apoptosis.
Voltage-gated potassium channels are essential in regulating neuronal membrane potential, and in contributing to action potential production and firing. In mammalian CNS neurons, KCNB1 is a predominant delayed rectifier potassium current that regulates neuronal excitability, action potential duration, and tonic spiking. This is necessary when it comes to proper neurotransmitter release, as such release is dependent on membrane potential. In mouse cardiomyocytes, KCNB1 channel is the molecular substrate of major repolarization current IK-slow2. Transgenic mice, expressing a dominant-negative isoform of KCNB1, exhibit markedly prolonged action potentials and demonstrate arrhythmia. KCNB1 also contributes to the function and regulation of smooth muscle fibers. Human studies on pulmonary arteries have shown that normal, physiological inhibition of KCNB1 current aids vasoconstriction of arteries. In human pancreatic ß cells, KCNB1, which mediates potassium efflux, produces a downstroke of the action potential in the cell. In effect, this behavior halts insulin secretion, as its activation decreases the Cav channel-mediated calcium influx that is necessary for insulin exocytosis. KCNB1 has also been found to promote apoptosis within neuronal cells. It is currently believed that KCNB1-induced apoptosis occurs in response to an increase in reactive oxygen species (ROS) that results either from acute oxidation or as a consequence of other cellular stresses.
# Regulation
KCNB1 conductance is regulated primarily by oligomerization and phosphorylation. Additional forms of regulation include SUMOylation and acetylation, although the direct effect of these modifications is still under investigation. KCNB1 consensus sites in the N-terminus are not subject to glycosylation.
## Phosphorylation
Many proteins undergo phosphorylation, or the addition of phosphate groups to amino acids subunits. Phosphorylation is modulated by kinases, which add phosphate groups, and phosphatases, which remove phosphate groups. In its phosphorylated state, KCNB1 is a poor conductor of current. There are 16 phosphorylation sites that are subject to the activity of kinases, such as cyclin-dependent kinase 5 and AMP-activated protein kinase. These sites are reversibly regulated by phosphatases such as, phosphatase calcineurin. Under periods of high electrical activity, depolarization of the neuron increases calcium influx and triggers phosphatase activity. Under resting conditions, KCNB1 tends to be phosphorylated. Phosphorylation raises the threshold voltage requirement for activation and allows microdomains to bind the channel, preventing KCNB1 from entering the plasma membrane. Microdomains localize KCNB1 in dendrites in cell bodies of hippocampal and cortical neurons. Conductance associated with de-phosphorylation of this channel acts to decrease or end periods high excitability. However, this relationship is not static and is cell dependent. The role of phosphorylation can be affected by reactive oxygen species (ROS) that increase during oxidative stress. ROS act to increase the levels of zinc (Zn2+) and calcium (Ca2+) intracellularly that act with protein kinases to phosphorylate certain sites on KCNB1. This phosphorylation increases the insertion of KCNB1 into the membrane and elevates conductance. Under these conditions the interaction with SNARE protein syntaxin, is enhanced. This surge of KCNB1 current induces activation of a pro-apoptotic pathway, DNA fragmentation, and caspase activation.
## Oligomerization
Another proposed mechanism for regulation of apoptosis is oligomerization, or the process of forming multi-protein complexes held together through disulfide bonds. Under oxidative stress, reactive oxygen species (ROS) form and act to regulate KCNB1 through oxidation. Increase in oxygen radicals directly causes formation of KCNB1 oligomers that then accumulate in the plasma membrane and initially decrease current flow . Oligomer activation of c-Src and JNK kinases induces the initial pro-apoptotic signal, which is coupled to KCNB1 current. This further promotes the apoptosis pathway . KCNB1 oligomers have been detected in the post mortem human hippocampus
# Blockers
Potassium delayed rectifiers have been implicated in many pharmacological uses in the investigation of biological toxins for drug development. A main component to many of the toxins with negative effects on delayed rectifiers contain cystine inhibitors that are arranged around disulfide bond formations. Many of these toxins originate from species of tarantulas. G. spatulata produces the hanatoxin, which was the first drug to be manipulated to interact with KCNB1 receptors by inhibiting the activation of most potassium voltage-gated channels. Other toxins, such as stromatoxin, heteroscordratoxin, and guangxitoxin, target the selectivity of voltage KCNB1 rectifiers, by either lowering potassium binding affinity or increasing the binding rate of potassium. This can lead to excitotoxicity, or overstimulation of postsynaptic neurons. In nature, the prey of tarantula that are injected with these endogenous toxins induces this excitotoxic effect, producing paralysis for easy capture. Physiologically, these venoms work on KCNB1 rectifier affinity by altering the channels’ voltage sensor, making it more or less sensitive to extracellular potassium concentrations. KCNB1 is also susceptible to tetraethylammonium (TEA) and 4-aminopyridine (4-AP), which completely block all channel activity. TEA also works on calcium-activated potassium channels, furthering its inhibitory effects on neurons and skeletal muscle. Some isoforms of TEA are beneficial for patients with severe Alzheimer’s, as blocking KCNB1 channels reduces the amount of neuronal apoptosis, thereby slowing the rate of dementia. This has been attributed to the oxidative properties of the channel by ROS.
# Physiological Role in Disease
## Neurodegenerative Disease
Oxidative damage is widely considered to play a role in neurodegenerative disorders, including Alzheimers disease. Such oxidative stress alters the redox sensitivity of the Kv2.1 delayed rectifier, resulting in the modulation of the channel. In vitro studies and studies in animal models show that when KCNB1 is oxidized, it no longer conducts, leading to neurons becoming hyperpolarized and dying; oxidized KCNB1 also clusters in lipid rafts and cannot be internalized, which also leads to apoptosis. These alterations disrupt normal neuronal signaling and increase the likelihood of neurological diseases. Oxidized (oligomerized) KCNB1 channels are present in the hippocampi of old (Braak stage 1-2) and Alzheimer's disease (Braak stage 5) donors of either sexes
Increased probability of the channel remaining open can also potentially drive neurodegeneration. Human immunodeficiency virus type-1 (HIV-1)-associated dementia (HAD) may be driven by an overabundance of glutamate, which in turn can trigger increased calcium levels, which in turn can drive calcium-dependent dephosphorylation of KCNB1 channels, which increases probability of channel activation and current conductance. Enhanced KCNB1 current couples cell shrinkage associated with apoptosis and dendritic beading leading to diminished long term potentiation. These neuronal modifications may explain the atrophy of cell layer volume and late stage cell death observed in HAD disease.
## Cancer
Exploitation of this channel is advantageous in cancer cell survival as they have the ability to produce heme oxygenase-1, an enzyme with the ability to generate carbon monoxide (CO). Oncogenic cells benefit from producing CO due to the antagonizing effects of the KCNB1 channel. Inhibition of KCNB1 allows cancer proliferation without the apoptotic pathway preventing tumor formation. Although potassium channels are studied as a therapeutic target for cancer, this apoptotic regulation is dependent on cancer type, potassium channel type, expression levels, intracellular localization as well as regulation by pro- or anti-apoptotic factors.
# Interactions
KCNB1 has been shown to interact with:
- KCNH1, and
- PTPRE. | KCNB1
Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein that, in humans, is encoded by the KCNB1 gene.[1][2][3]
Potassium voltage-gated channel subfamily B member one, or simply known as KCNB1, is a delayed rectifier and voltage-gated potassium channel found throughout the body. The channel has a diverse number of functions. However, its main function, as a delayed rectifier, is to propagate current in its respective location. It is commonly expressed in the central nervous system, but may also be found in pulmonary arteries, auditory outer hair cells, stem cells, the retina, and organs such as the heart and pancreas. Modulation of K+ channel activity and expression has been found to be at the crux of many profound pathophysiological disorders in several cell types.[4]
Potassium channels are among the most diverse of all ion channels in eukaryotes. With over 100 genes coding numerous functions, many isoforms of potassium channels are present in the body, but most are divided up into two main groups: inactivating transient channels and non-inactivating delayed rectifiers. Due to the multiple varied forms, potassium delayed rectifier channels open or close in response to a myriad of signals. These include: cell depolarization or hyperpolarization, increases in intracellular calcium concentrations, neurotransmitter binding, or second messenger activity such as G-proteins or kinases.[5]
# Structure
The general structure of all potassium channels contain a centered pore composed of alpha subunits with a pore loop expressed by a segment of conserved DNA, T/SxxTxGxG. This general sequence comprises the selectivity of the potassium channel. Depending on the channel, the alpha subunits are constructed in either a homo- or hetero-association, creating a 4-subunit selectivity pore or a 2-subunit pore, each with accessory beta subunits attached intracellularly. Also on the cytoplasmic side are the N- and C- termini, which play a crucial role in activating and deactivating KCNB1 channels. This pore creates the main opening of the channel where potassium ions flow through.[6]
The type of pore domain (number of subunits) determines if the channel has the typical 6 transmembrane (protein) spanning regions, or the less dominant inward rectifier type of only 2 regions. KCNB1 has 6TM labeled S1-S6, each with a tetrameric structure. S5 and S6 create the p-loop, while S4 is the location of the voltage sensor. S4, along with S2 and S3 create the ‘activating’ portions of the delayed rectifier channel.[6] The heteromeric complexes that contain the distinct pore are electrically inactive or non-conducting, but unlike other potassium families, the pore of the KCNB1 group has numerous phosphorylation sites allowing kinase activity. Maturing KCNB1 channels develop these phosphorylation sites within the channel pore, but lack a glycosylation stage in the N-terminus.[7]
Specifically, the KCNB1 delayed rectifier channel conducts a potassium current (K+). This mediates high frequency firing due to the phosphorylation sites located within the channel via kinases and a major calcium influx typical of all neurons.[7]
## Kinetics
The kinetics surrounding the activation and deactivation of the KCNB1 channel is relatively unknown, and has been under considerable study. Three of the six transmembrane regions, S2, S3 and S4, contribute to the activation phase of the channel. Upon depolarization, the S4 region, which is positively charged, is moved in response to the subsequent positive charge of the depolarization. As a result of S4 movement, the negatively charged regions of S2 and S3 appear to move as well.[6] The movement of these regions causes an opening of the channel gate within regions of S5 and S6.[8] The intracellular regions of the C and N-terminus also play a crucial role in the activation kinetics of the channel. The two termini interact with one other, as the C-terminus folds around the N-terminus during channel activation. The relative movement between the N- and C- termini greatly aids in producing a conformational change of the channel necessary for channel opening. This interaction between these intracellular regions is believed to be linked with membrane-spanning regions of S1 and S6, and thus aid in the movement of S2, S3, and S4 in opening the channel.[6][8] Studies on selective mutations knocking out these intracellular termini have been shown to produce larger reductions in speed and probability of channel opening, which indicates their importance in channel activation.[6]
# Function
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints.[1] Delayed rectifier potassium channels’ most prevalent role is in the falling phase of physiological action potentials. KCNB1 rectifiers are also important in forming the cardiac beat and rate synchronicity that exists within the heart, and the lysis of target molecules in the immune response. These channels can also act as effectors in downstream signaling in G-protein coupled receptor transduction. KCNB1’s regulation and propagation of current provides a means for regulatory control over several physiological functions.[5] Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and apoptosis.[1]
Voltage-gated potassium channels are essential in regulating neuronal membrane potential, and in contributing to action potential production and firing.[9] In mammalian CNS neurons, KCNB1 is a predominant delayed rectifier potassium current that regulates neuronal excitability, action potential duration, and tonic spiking. This is necessary when it comes to proper neurotransmitter release, as such release is dependent on membrane potential. In mouse cardiomyocytes, KCNB1 channel is the molecular substrate of major repolarization current IK-slow2. Transgenic mice, expressing a dominant-negative isoform of KCNB1, exhibit markedly prolonged action potentials and demonstrate arrhythmia.[10] KCNB1 also contributes to the function and regulation of smooth muscle fibers. Human studies on pulmonary arteries have shown that normal, physiological inhibition of KCNB1 current aids vasoconstriction of arteries.[11] In human pancreatic ß cells, KCNB1, which mediates potassium efflux, produces a downstroke of the action potential in the cell.[12] In effect, this behavior halts insulin secretion, as its activation decreases the Cav channel-mediated calcium influx that is necessary for insulin exocytosis. KCNB1 has also been found to promote apoptosis within neuronal cells. It is currently believed that KCNB1-induced apoptosis occurs in response to an increase in reactive oxygen species (ROS) that results either from acute oxidation or as a consequence of other cellular stresses.[7]
# Regulation
KCNB1 conductance is regulated primarily by oligomerization and phosphorylation. Additional forms of regulation include SUMOylation and acetylation, although the direct effect of these modifications is still under investigation. KCNB1 consensus sites in the N-terminus are not subject to glycosylation.[4]
## Phosphorylation
Many proteins undergo phosphorylation, or the addition of phosphate groups to amino acids subunits. Phosphorylation is modulated by kinases, which add phosphate groups, and phosphatases, which remove phosphate groups. In its phosphorylated state, KCNB1 is a poor conductor of current. There are 16 phosphorylation sites that are subject to the activity of kinases, such as cyclin-dependent kinase 5 and AMP-activated protein kinase. These sites are reversibly regulated by phosphatases such as, phosphatase calcineurin. Under periods of high electrical activity, depolarization of the neuron increases calcium influx and triggers phosphatase activity. Under resting conditions, KCNB1 tends to be phosphorylated. Phosphorylation raises the threshold voltage requirement for activation and allows microdomains to bind the channel, preventing KCNB1 from entering the plasma membrane. Microdomains localize KCNB1 in dendrites in cell bodies of hippocampal and cortical neurons. Conductance associated with de-phosphorylation of this channel acts to decrease or end periods high excitability. However, this relationship is not static and is cell dependent. The role of phosphorylation can be affected by reactive oxygen species (ROS) that increase during oxidative stress. ROS act to increase the levels of zinc (Zn2+) and calcium (Ca2+) intracellularly that act with protein kinases to phosphorylate certain sites on KCNB1. This phosphorylation increases the insertion of KCNB1 into the membrane and elevates conductance. Under these conditions the interaction with SNARE protein syntaxin, is enhanced. This surge of KCNB1 current induces activation of a pro-apoptotic pathway, DNA fragmentation, and caspase activation.[4]
## Oligomerization
Another proposed mechanism for regulation of apoptosis is oligomerization, or the process of forming multi-protein complexes held together through disulfide bonds. Under oxidative stress, reactive oxygen species (ROS) form and act to regulate KCNB1 through oxidation. Increase in oxygen radicals directly causes formation of KCNB1 oligomers that then accumulate in the plasma membrane and initially decrease current flow [13][14]. Oligomer activation of c-Src and JNK kinases induces the initial pro-apoptotic signal, which is coupled to KCNB1 current. This further promotes the apoptosis pathway [15]. KCNB1 oligomers have been detected in the post mortem human hippocampus [16]
# Blockers
Potassium delayed rectifiers have been implicated in many pharmacological uses in the investigation of biological toxins for drug development. A main component to many of the toxins with negative effects on delayed rectifiers contain cystine inhibitors that are arranged around disulfide bond formations. Many of these toxins originate from species of tarantulas. G. spatulata produces the hanatoxin, which was the first drug to be manipulated to interact with KCNB1 receptors by inhibiting the activation of most potassium voltage-gated channels. Other toxins, such as stromatoxin, heteroscordratoxin, and guangxitoxin, target the selectivity of voltage KCNB1 rectifiers, by either lowering potassium binding affinity or increasing the binding rate of potassium. This can lead to excitotoxicity, or overstimulation of postsynaptic neurons. In nature, the prey of tarantula that are injected with these endogenous toxins induces this excitotoxic effect, producing paralysis for easy capture. Physiologically, these venoms work on KCNB1 rectifier affinity by altering the channels’ voltage sensor, making it more or less sensitive to extracellular potassium concentrations.[17] KCNB1 is also susceptible to tetraethylammonium (TEA) and 4-aminopyridine (4-AP), which completely block all channel activity. TEA also works on calcium-activated potassium channels, furthering its inhibitory effects on neurons and skeletal muscle. Some isoforms of TEA are beneficial for patients with severe Alzheimer’s, as blocking KCNB1 channels reduces the amount of neuronal apoptosis, thereby slowing the rate of dementia.[18] This has been attributed to the oxidative properties of the channel by ROS.[5]
# Physiological Role in Disease
## Neurodegenerative Disease
Oxidative damage is widely considered to play a role in neurodegenerative disorders, including Alzheimers disease. Such oxidative stress alters the redox sensitivity of the Kv2.1 delayed rectifier, resulting in the modulation of the channel.[4] In vitro studies and studies in animal models show that when KCNB1 is oxidized, it no longer conducts, leading to neurons becoming hyperpolarized and dying; oxidized KCNB1 also clusters in lipid rafts and cannot be internalized, which also leads to apoptosis. These alterations disrupt normal neuronal signaling and increase the likelihood of neurological diseases. Oxidized (oligomerized) KCNB1 channels are present in the hippocampi of old (Braak stage 1-2) and Alzheimer's disease (Braak stage 5) donors of either sexes [19] [20]
Increased probability of the channel remaining open can also potentially drive neurodegeneration. Human immunodeficiency virus type-1 (HIV-1)-associated dementia (HAD) may be driven by an overabundance of glutamate, which in turn can trigger increased calcium levels, which in turn can drive calcium-dependent dephosphorylation of KCNB1 channels, which increases probability of channel activation and current conductance. Enhanced KCNB1 current couples cell shrinkage associated with apoptosis and dendritic beading leading to diminished long term potentiation. These neuronal modifications may explain the atrophy of cell layer volume and late stage cell death observed in HAD disease.[21]
## Cancer
Exploitation of this channel is advantageous in cancer cell survival as they have the ability to produce heme oxygenase-1, an enzyme with the ability to generate carbon monoxide (CO). Oncogenic cells benefit from producing CO due to the antagonizing effects of the KCNB1 channel. Inhibition of KCNB1 allows cancer proliferation without the apoptotic pathway preventing tumor formation. Although potassium channels are studied as a therapeutic target for cancer, this apoptotic regulation is dependent on cancer type, potassium channel type, expression levels, intracellular localization as well as regulation by pro- or anti-apoptotic factors. [22]
# Interactions
KCNB1 has been shown to interact with:
- KCNH1,[23] and
- PTPRE.[24] | https://www.wikidoc.org/index.php/KCNB1 | |
2093bf1c4aadae522c2993018b00343b5bd5f413 | wikidoc | KCNC1 | KCNC1
Potassium voltage-gated channel subfamily C member 1 is a protein that in humans is encoded by the KCNC1 gene.
The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and comprises four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes.
# Expression pattern
Kv3.1 and Kv3.2 channels are prominently expressed in neurons that fire at high frequency. Kv3.1 channels are prominently expressed in brain (cerebellum > globus pallidus, subthalamic nucleus, substantia nigra > reticular thalamic nuclei, cortical and hippocampal interneurons > inferior colliculi, cochlear and vestibular nuclei), and in retinal ganglion cells.
# Physiological role
Kv3.1/Kv3.2 conductance is necessary and kinetically optimized for high-frequency action potential generation. Kv3.1 channels are important for the high-firing frequency of auditory and fast-spiking GABAergic interneurons, retinal ganglion cells; regulation of action potential duration in presynaptic terminals.
# Pharmacological properties
Kv3.1 currents in heterologous systems are highly sensitive to external tetraethylammonium (TEA) or 4-aminopyridine (4-AP) (IC50 values are 0.2 mM and 29 μM respectively). This can be useful in identifying native channels. The overlapping sensitivity of potassium current to both 0.5 mM TEA and 30 μM 4-AP strongly suggest an action on Kv3.1 subunits.
# Transcript variants
There are two transcript variants of Kv3.1 gene: Kv3.1a and Kv3.1b. Kv3.1 isoforms differ only in their C-terminal sequence.
# Clinical significance
A missense mutation c.959G>A (p.Arg320His) in KCNC1 causes progressive myoclonus epilepsy. | KCNC1
Potassium voltage-gated channel subfamily C member 1 is a protein that in humans is encoded by the KCNC1 gene.[1][2][3]
The Shaker gene family of Drosophila encodes components of voltage-gated potassium channels and comprises four subfamilies. Based on sequence similarity, this gene is similar to one of these subfamilies, namely the Shaw subfamily. The protein encoded by this gene belongs to the delayed rectifier class of channel proteins and is an integral membrane protein that mediates the voltage-dependent potassium ion permeability of excitable membranes.[3]
# Expression pattern
Kv3.1 and Kv3.2 channels are prominently expressed in neurons that fire at high frequency. Kv3.1 channels are prominently expressed in brain (cerebellum > globus pallidus, subthalamic nucleus, substantia nigra > reticular thalamic nuclei, cortical and hippocampal interneurons > inferior colliculi, cochlear and vestibular nuclei), and in retinal ganglion cells.[4][5][6]
# Physiological role
Kv3.1/Kv3.2 conductance is necessary and kinetically optimized for high-frequency action potential generation.[5][7] Kv3.1 channels are important for the high-firing frequency of auditory and fast-spiking GABAergic interneurons, retinal ganglion cells; regulation of action potential duration in presynaptic terminals.[4][6]
# Pharmacological properties
Kv3.1 currents in heterologous systems are highly sensitive to external tetraethylammonium (TEA) or 4-aminopyridine (4-AP) (IC50 values are 0.2 mM and 29 μM respectively).[5][6] This can be useful in identifying native channels.[5] The overlapping sensitivity of potassium current to both 0.5 mM TEA and 30 μM 4-AP strongly suggest an action on Kv3.1 subunits.[8]
# Transcript variants
There are two transcript variants of Kv3.1 gene: Kv3.1a and Kv3.1b. Kv3.1 isoforms differ only in their C-terminal sequence.[9]
# Clinical significance
A missense mutation c.959G>A (p.Arg320His) in KCNC1 causes progressive myoclonus epilepsy.[10] | https://www.wikidoc.org/index.php/KCNC1 | |
8e6d22bd9c6f7997db188d2f768fc6107fd34830 | wikidoc | KCNC2 | KCNC2
Potassium voltage-gated channel subfamily C member 2 is a protein that in humans is encoded by the KCNC2 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit (Kv3.2).
# Expression pattern
Kv3.1 and Kv3.2 channels are prominently expressed in neurons that fire at high frequency. Kv3.2 channels are prominently expressed in brain (fast-spiking GABAergic interneurons of the neocortex, hippocampus, and caudate nucleus; terminal fields of thalamocortical projections), and in retinal ganglion cells.
# Physiological role
Kv3.1/Kv3.2 conductance is necessary and kinetically optimized for high-frequency action potential generation. Sometimes in heteromeric complexes with Kv3.1; important for the high-frequency firing of fast spiking GABAergic interneurons and retinal ganglion cells; and GABA release via regulation of action potential duration in presynaptic terminals.
# Pharmacological properties
Kv3.2 currents in heterologous systems are highly sensitive to external tetraethylammonium (TEA) or 4-aminopyridine (4-AP) (IC50 values are 0.1 mM for both of the drugs). This can be useful in identifying native channels.
# Transcript variants
There are four transcript variants of Kv3.2 gene: Kv3.2a, Kv3.2b, Kv3.2c, Kv3.2d. Kv3.2 isoforms differ only in their C-terminal sequence. | KCNC2
Potassium voltage-gated channel subfamily C member 2 is a protein that in humans is encoded by the KCNC2 gene.[1][1][2] The protein encoded by this gene is a voltage-gated potassium channel subunit (Kv3.2).[3]
# Expression pattern
Kv3.1 and Kv3.2 channels are prominently expressed in neurons that fire at high frequency. Kv3.2 channels are prominently expressed in brain (fast-spiking GABAergic interneurons of the neocortex, hippocampus, and caudate nucleus; terminal fields of thalamocortical projections), and in retinal ganglion cells.[4][5][3]
# Physiological role
Kv3.1/Kv3.2 conductance is necessary and kinetically optimized for high-frequency action potential generation.[5][6] Sometimes in heteromeric complexes with Kv3.1; important for the high-frequency firing of fast spiking GABAergic interneurons and retinal ganglion cells; and GABA release via regulation of action potential duration in presynaptic terminals.[3][4]
# Pharmacological properties
Kv3.2 currents in heterologous systems are highly sensitive to external tetraethylammonium (TEA) or 4-aminopyridine (4-AP) (IC50 values are 0.1 mM for both of the drugs).[3][5] This can be useful in identifying native channels.[5]
# Transcript variants
There are four transcript variants of Kv3.2 gene: Kv3.2a, Kv3.2b, Kv3.2c, Kv3.2d. Kv3.2 isoforms differ only in their C-terminal sequence.[7] | https://www.wikidoc.org/index.php/KCNC2 | |
e352db1070553180e844ba05aec25859a73bbb8d | wikidoc | KCND3 | KCND3
Potassium voltage-gated channel subfamily D member 3 also known as Kv4.3 is a protein that in humans is encoded by the KCND3 gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.
# Function
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes – shaker, shaw, shab, and shal – have been identified in Drosophila, and each has been shown to have human homolog(s).
Kv4.3 is a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene.
# Clinical significance
Gain of function is believed to cause Brugada Syndrome although only indirectly shown by mutations in the beta subunit KCNE3 which causes gain of function of Kv4.3. | KCND3
Potassium voltage-gated channel subfamily D member 3 also known as Kv4.3 is a protein that in humans is encoded by the KCND3 gene.[1][2][3] It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.[4]
# Function
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes – shaker, shaw, shab, and shal – have been identified in Drosophila, and each has been shown to have human homolog(s).
Kv4.3 is a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member includes two isoforms with different sizes, which are encoded by alternatively spliced transcript variants of this gene.[3]
# Clinical significance
Gain of function is believed to cause Brugada Syndrome although only indirectly shown by mutations in the beta subunit KCNE3 which causes gain of function of Kv4.3. | https://www.wikidoc.org/index.php/KCND3 | |
1aacdac40b5f3a9616969da19d945761043ec5b5 | wikidoc | KCNE1 | KCNE1
Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.
Voltage-gated potassium channels (Kv) represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume.
KCNE1 is one of five members of the KCNE family of Kv channel ancillary or β subunits. It is also known as minK (minimal potassium channel subunit).
# Function
KCNE1 is primarily known for modulating the cardiac and epithelial Kv channel α subunit, KCNQ1. KCNQ1 and KCNE1 form a complex in human ventricular cardiomyocytes that generates the slowly activating K+ current, IKs. Together with the rapidly activating K+ current (IKr), IKs is important for human ventricular repolarization. KCNQ1 is also essential for the normal function of many different epithelial tissues, but in these non-excitable cells it is thought to be predominantly regulated by KCNE2 or KCNE3.
KCNE1 slows the activation of KCNQ1 5-10 fold, increases its unitary conductance 4-fold, eliminates its inactivation, and alters the manner in which KCNQ1 is regulated by other proteins, lipids and small molecules. The association of KCNE1 with KCNQ1 was discovered 8 years after Takumi and colleagues reported the isolation of a fraction of RNA from rat kidney that, when injected into Xenopus oocytes, produced an unusually slow-activating, voltage-dependent, potassium-selective current. Takumi et al discovered the KCNE1 gene and it was correctly predicted to encode a single-transmembrane domain protein with an extracellular N-terminal domain and a cytosolic C-terminal domain. The ability of KCNE1 to generate this current was confusing because of its simple primary structure and topology, contrasting with the 6-transmembrane domain topology of other known Kv α subunits such as Shaker from Drosophila, cloned 2 years earlier. The mystery was solved when KCNQ1 was cloned and found to co-assemble with KCNE1, and it was shown that Xenopus laevis oocytes endogenously express KCNQ1, which is upregulated by exogenous expression of KCNE1 to generate the characteristic slowly activating current., KCNQ1 is also essential for the normal function of many different epithelial tissues, but in these non-excitable cells it is thought to be predominantly regulated by KCNE2 or KCNE3.
KCNE1 is also reported to regulate two other KCNQ family α subunits, KCNQ4 and KCNQ5. KCNE1 increased both their peak currents in oocyte expression studies, and slowed the activation of the latter.,
KCNE1 also regulates hERG, which is the Kv α subunit that generates ventricular IKr. KCNE1 doubled hERG current when the two were expressed in mammalian cells, although the mechanism for this remains unknown.
Although KCNE1 had no effect when co-expressed with the Kv1.1 α subunit in Chinese Hamster ovary (CHO) cells, KCNE1 traps the N-type (rapidly inactivating) Kv1.4 α subunit in the ER/Golgi when co-expressed with it. KCNE1 (and KCNE2) also has this effect on the two other canonical N-type Kv α subunits, Kv3.3 and Kv3.4. This appears to be a mechanism for ensuring that homomeric N-type channels do not reach the cell surface, as this mode of suppression by KCNE1 or KCNE2 is relieved by co-expression of same-subfamily delayed rectifier (slowly inactivating) α subunits. Thus, Kv1.1 rescued Kv1.4, Kv3.1 rescued Kv3.4; in each of these cases the resultant channels at the membrane were heteromers (e.g., Kv3.1-Kv3.4) and displayed intermediate inactivation kinetics to those of either α subunit alone.,
KCNE1 also regulates the gating kinetics of Kv2.1, Kv3.1 and Kv3.2, in each case slowing their activation and deactivation, and accelerating inactivation of the latter two., No effects were observed upon oocyte co-expression of KCNE1 and Kv4.2, but KCNE1 was found to slow the gating and increase macroscopic current of Kv4.3 in HEK cells. In contrast, channels formed by Kv4.3 and the cytosolic ancillary subunit KChIP2 exhibited faster activation and altered inactivation when co-expressed with KCNE1 in CHO cells. Finally, KCNE1 inhibited Kv12.2 in Xenopus oocytes.
# Structure
The large majority of studies into the structural basis for KCNE1 modulation of Kv channels focus on its interaction with KCNQ1 (previously named KvLQT1). Residues in the transmembrane domain of KCNE1 lies close to the selectivity filter of KCNQ1 within heteromeric KCNQ1-KCNE1 channel complexes., The C-terminal domain of KCNE1, specifically from amino acids 73 to 79 is necessary for stimulation of slow delayed potassium rectifier current by SGK1. The interaction of KCNE1 with an alpha helix in the S6 KvLQT1 domain contributes to the higher affinity this channel has for benzodiazepine L7 and chromanol 293B by repositioning amino acid residues to allow for this. KCNE1 destabilizes the S4-S5 alpha-helix linkage in the KCNQ1 channel protein in addition to destabilizing the S6 alpha helix, leading to slower activation of this channel when associated with KCNE1. Variable stohiometries have been discussed but there are probably 2 KCNE1 subunits and 4 KCNQ1 subunits in a plasma membrane IKs complex.
The transmembrane segment of KCNE1 is α-helical when in a membrane environment., The transmembrane segment of KCNE1 has been suggested to interact with the KCNQ1 pore domain (S5/S6) and with the S4 domain of the KCNQ1 (KvLQT1) channel. KCNE1 may bind to the outer part of the KCNQ1 pore domain, and slide from this position into the “activation cleft” which leads to greater current amplitudes
KCNE1 slows KCNQ1 activation several-fold, and there are ongoing discussions about the precise mechanisms underlying this. In a study in which KCNQ1 voltage sensor movement was monitored by site-directed fluorimetry and also by measuring the charge displacement associated with movement of charges within the S4 segment of the voltage sensor (gating current), KCNE1 was found to slow S4 movement so much that the gating current was no longer measurable. Fluorimetry measurements indicated that KCNQ1-KCNE1 channel S4 movement was 30-fold slower than that of the well-studied Drosophila Shaker Kv channel. Nakajo and Kubo found that KCNE1 either slowed KCNQ1 S4 movement upon membrane depolarization, or altered S4 equilibrium at a given membrane potential. The Kass lab deduced that while homomeric KCNQ1 channels can open after the movement of a single S4 segment, KCNQ1-KCNE1 channels can only open after all four S4 segments have been activated. The intracellular C-terminal domain of KCNE1 is thought to sit on the KCNQ1 S4-S5 linker, a segment of KCNQ1 crucial for communicating S4 status to the pore and thus control activation.
# Tissue distribution
KCNE1 is expressed in human heart (atria and ventricles), whereas in adult mouse heart its expression appears limited to the atria and/or conduction system. KCNE1 is also expressed in human and musine inner ear and kidneys. KCNE1 has been detected in mouse brain but this finding is a subject of ongoing debate.
# Clinical significance
Inherited or sporadic KCNE gene mutations can cause Romano-Ward syndrome (heterozygotes) and Jervell Lange-Nielsens syndrome (homozygotes). Both these syndromes are characterized by Long QT syndrome, a delay in ventricular repolarization. In addition, Jervell and Lange-Nielsen syndrome also involves bilateral sensorineural deafness. Mutation D76N in the KCNE1 protein can lead to long QT syndrome due to structural changes in the KvLQT1/KCNE1 complex, and people with these mutations are advised to avoid triggers of cardiac arrhythmia and prolonged QT intervals, such as stress or strenuous exercise.
While loss-of-function mutations in KCNE1 cause Long QT syndrome, gain-of-function KCNE1 mutations are associated with early-onset atrial fibrillation. A common KCNE1 polymorphism, S38G, is associated with altered predisposition to lone atrial fibrillation and postoperative atrial fibrillation. Atrial KCNE1 expression was downregulated in a porcine model of post-operative atrial fibrillation following lung lobectomy. | KCNE1
Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.[1][2]
Voltage-gated potassium channels (Kv) represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume.
KCNE1 is one of five members of the KCNE family of Kv channel ancillary or β subunits. It is also known as minK (minimal potassium channel subunit).
# Function
KCNE1 is primarily known for modulating the cardiac and epithelial Kv channel α subunit, KCNQ1. KCNQ1 and KCNE1 form a complex in human ventricular cardiomyocytes that generates the slowly activating K+ current, IKs. Together with the rapidly activating K+ current (IKr), IKs is important for human ventricular repolarization.[3][4] KCNQ1 is also essential for the normal function of many different epithelial tissues, but in these non-excitable cells it is thought to be predominantly regulated by KCNE2 or KCNE3.[5]
KCNE1 slows the activation of KCNQ1 5-10 fold, increases its unitary conductance 4-fold, eliminates its inactivation, and alters the manner in which KCNQ1 is regulated by other proteins, lipids and small molecules. The association of KCNE1 with KCNQ1 was discovered 8 years after Takumi and colleagues reported the isolation of a fraction of RNA from rat kidney that, when injected into Xenopus oocytes, produced an unusually slow-activating, voltage-dependent, potassium-selective current. Takumi et al discovered the KCNE1 gene[6] and it was correctly predicted to encode a single-transmembrane domain protein with an extracellular N-terminal domain and a cytosolic C-terminal domain. The ability of KCNE1 to generate this current was confusing because of its simple primary structure and topology, contrasting with the 6-transmembrane domain topology of other known Kv α subunits such as Shaker from Drosophila, cloned 2 years earlier. The mystery was solved when KCNQ1 was cloned and found to co-assemble with KCNE1, and it was shown that Xenopus laevis oocytes endogenously express KCNQ1, which is upregulated by exogenous expression of KCNE1 to generate the characteristic slowly activating current.,[3][4] KCNQ1 is also essential for the normal function of many different epithelial tissues, but in these non-excitable cells it is thought to be predominantly regulated by KCNE2 or KCNE3.[5]
KCNE1 is also reported to regulate two other KCNQ family α subunits, KCNQ4 and KCNQ5. KCNE1 increased both their peak currents in oocyte expression studies, and slowed the activation of the latter.,[7][8]
KCNE1 also regulates hERG, which is the Kv α subunit that generates ventricular IKr. KCNE1 doubled hERG current when the two were expressed in mammalian cells, although the mechanism for this remains unknown.[9]
Although KCNE1 had no effect when co-expressed with the Kv1.1 α subunit in Chinese Hamster ovary (CHO) cells, KCNE1 traps the N-type (rapidly inactivating) Kv1.4 α subunit in the ER/Golgi when co-expressed with it. KCNE1 (and KCNE2) also has this effect on the two other canonical N-type Kv α subunits, Kv3.3 and Kv3.4. This appears to be a mechanism for ensuring that homomeric N-type channels do not reach the cell surface, as this mode of suppression by KCNE1 or KCNE2 is relieved by co-expression of same-subfamily delayed rectifier (slowly inactivating) α subunits. Thus, Kv1.1 rescued Kv1.4, Kv3.1 rescued Kv3.4; in each of these cases the resultant channels at the membrane were heteromers (e.g., Kv3.1-Kv3.4) and displayed intermediate inactivation kinetics to those of either α subunit alone.,[10][11]
KCNE1 also regulates the gating kinetics of Kv2.1, Kv3.1 and Kv3.2, in each case slowing their activation and deactivation, and accelerating inactivation of the latter two.,[12][13] No effects were observed upon oocyte co-expression of KCNE1 and Kv4.2,[14] but KCNE1 was found to slow the gating and increase macroscopic current of Kv4.3 in HEK cells.[15] In contrast, channels formed by Kv4.3 and the cytosolic ancillary subunit KChIP2 exhibited faster activation and altered inactivation when co-expressed with KCNE1 in CHO cells.[16] Finally, KCNE1 inhibited Kv12.2 in Xenopus oocytes.[17]
# Structure
The large majority of studies into the structural basis for KCNE1 modulation of Kv channels focus on its interaction with KCNQ1 (previously named KvLQT1). Residues in the transmembrane domain of KCNE1 lies close to the selectivity filter of KCNQ1 within heteromeric KCNQ1-KCNE1 channel complexes.,[18][19] The C-terminal domain of KCNE1, specifically from amino acids 73 to 79 is necessary for stimulation of slow delayed potassium rectifier current by SGK1.[20] The interaction of KCNE1 with an alpha helix in the S6 KvLQT1 domain contributes to the higher affinity this channel has for benzodiazepine L7 and chromanol 293B by repositioning amino acid residues to allow for this. KCNE1 destabilizes the S4-S5 alpha-helix linkage in the KCNQ1 channel protein in addition to destabilizing the S6 alpha helix, leading to slower activation of this channel when associated with KCNE1.[21] Variable stohiometries have been discussed but there are probably 2 KCNE1 subunits and 4 KCNQ1 subunits in a plasma membrane IKs complex.[22]
The transmembrane segment of KCNE1 is α-helical when in a membrane environment.,[23][24] The transmembrane segment of KCNE1 has been suggested to interact with the KCNQ1 pore domain (S5/S6) and with the S4 domain of the KCNQ1 (KvLQT1) channel.[18] KCNE1 may bind to the outer part of the KCNQ1 pore domain, and slide from this position into the “activation cleft” which leads to greater current amplitudes[20]
KCNE1 slows KCNQ1 activation several-fold, and there are ongoing discussions about the precise mechanisms underlying this. In a study in which KCNQ1 voltage sensor movement was monitored by site-directed fluorimetry and also by measuring the charge displacement associated with movement of charges within the S4 segment of the voltage sensor (gating current), KCNE1 was found to slow S4 movement so much that the gating current was no longer measurable. Fluorimetry measurements indicated that KCNQ1-KCNE1 channel S4 movement was 30-fold slower than that of the well-studied Drosophila Shaker Kv channel.[25] Nakajo and Kubo found that KCNE1 either slowed KCNQ1 S4 movement upon membrane depolarization, or altered S4 equilibrium at a given membrane potential.[26] The Kass lab deduced that while homomeric KCNQ1 channels can open after the movement of a single S4 segment, KCNQ1-KCNE1 channels can only open after all four S4 segments have been activated.[27] The intracellular C-terminal domain of KCNE1 is thought to sit on the KCNQ1 S4-S5 linker, a segment of KCNQ1 crucial for communicating S4 status to the pore and thus control activation.[28]
# Tissue distribution
KCNE1 is expressed in human heart (atria and ventricles), whereas in adult mouse heart its expression appears limited to the atria and/or conduction system.[29] KCNE1 is also expressed in human and musine inner ear[30] and kidneys.[31] KCNE1 has been detected in mouse brain[32] but this finding is a subject of ongoing debate.
# Clinical significance
Inherited or sporadic KCNE gene mutations can cause Romano-Ward syndrome (heterozygotes) and Jervell Lange-Nielsens syndrome (homozygotes). Both these syndromes are characterized by Long QT syndrome, a delay in ventricular repolarization. In addition, Jervell and Lange-Nielsen syndrome also involves bilateral sensorineural deafness. Mutation D76N in the KCNE1 protein can lead to long QT syndrome due to structural changes in the KvLQT1/KCNE1 complex, and people with these mutations are advised to avoid triggers of cardiac arrhythmia and prolonged QT intervals, such as stress or strenuous exercise.[20]
While loss-of-function mutations in KCNE1 cause Long QT syndrome, gain-of-function KCNE1 mutations are associated with early-onset atrial fibrillation.[33] A common KCNE1 polymorphism, S38G, is associated with altered predisposition to lone atrial fibrillation[34] and postoperative atrial fibrillation.[35] Atrial KCNE1 expression was downregulated in a porcine model of post-operative atrial fibrillation following lung lobectomy.[36] | https://www.wikidoc.org/index.php/KCNE1 | |
e2db84f6ea4a929f6d58789404a41dd95b93350a | wikidoc | KCNE2 | KCNE2
Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21. MiRP1 is a voltage-gated potassium channel accessory subunit (beta subunit) associated with Long QT syndrome. It is ubiquitously expressed in many tissues and cell types. Because of this and its ability to regulate multiple different ion channels, KCNE2 exerts considerable influence on a number of cell types and tissues. Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellular N-terminal and intracellular C-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias. The KCNE2 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.
# Discovery
Steve Goldstein (then at Yale University) used a BLAST search strategy, focusing on KCNE1 sequence stretches known to be important for function, to identify related expressed sequence tags (ESTs) in the NCBI database. Using sequences from these ESTs, KCNE2, 3 and 4 were cloned.
# Tissue distribution
KCNE2 protein is most readily detected in the choroid plexus epithelium, gastric parietal cells, and thyroid epithelial cells. KCNE2 is also expressed in atrial and ventricular cardiomyocytes, the pancreas, pituitary gland, and lung epithelium. In situ hybridization data suggest that KCNE2 transcript may also be expressed in various neuronal populations.
# Structure
## Gene
The KCNE2 gene resides on chromosome 21 at the band 21q22.11 and contains 2 exons. Since human KCNE2 is located ~79 kb from KCNE1 and in the opposite direction, KCNE2 is proposed to originate from a gene duplication event.
## Protein
This protein belongs to the potassium channel KCNE family and is one five single transmembrane domain voltage-gated potassium (Kv) channel ancillary subunits. KCNE2 is composed of three major domains: the N-terminal domain, the transmembrane domain, and the C-terminal domain. The N-terminal domain protrudes out of the extracellular side of the cell membrane and is, thus, soluble in the aqueous environment. Meanwhile, the transmembrane and C-terminal domains are lipid-soluble to enable the protein to incorporate into the cell membrane. The C-terminal faces the intracellular side of the membrane and may share a putative PKC phosphorylation site with other KCNE proteins.
Like other KCNEs, KCNE2 forms a heteromeric complex with the Kv α subunits.
# Function
## Choroid plexus epithelium
KCNE2 protein is most readily detected in the choroid plexus epithelium, at the apical side. KCNE2 forms complexes there with the voltage-gated potassium channel α subunit, Kv1.3. In addition, KCNE2 forms reciprocally regulating tripartite complexes in the choroid plexus epithelium with the KCNQ1 α subunit and the sodium-dependent myo-inositol transporter, SMIT1. Kcne2-/- mice exhibit increased seizure susceptibility, reduced immobility time in the tail suspension test, and reduced cerebrospinal fluid myo-inositol content, compared to wild-type littermates. Mega-dosing of myo-inositol reverses all these phenotypes, suggesting a link between myo-inositol and the seizure susceptibility and behavioral alterations in Kcne2-/- mice.
## Gastric epithelium
KCNE2 is also highly expressed in parietal cells of the gastric epithelium, also at the apical side. In these cells, KCNQ1-KCNE2 K+ channels, which are constitutively active, provide a conduit to return K+ ions back to the stomach lumen. The K+ ions enter the parietal cell through the gastric H+/K+-ATPase, which swaps them for protons as it acidifies the stomach. While KCNQ1 channels are inhibited by low extracellular pH, KCNQ1-KCNE2 channels activity is augmented by extracellular protons, an ideal characteristic for their role in parietal cells.
## Thyroid epithelium
KCNE2 forms constitutively active K+ channels with KCNQ1 in the basolateral membrane of thyroid epithelial cells. Kcne2-/- mice exhibit hypothyroidism, particularly apparent during gestation or lactation. KCNQ1-KCNE2 is required for optimal iodide uptake into the thyroid by the basolateral sodium iodide symporter (NIS). Iodide is required for biosynthesis of thyroid hormones.
## Heart
KCNE2 was originally discovered to regulate hERG channel function. KCNE2 decreases marcoscopic and unitary current through hERG, and speeds hERG deactivation. hERG generates IKr, the most prominent repolarizing current in human ventricular cardiomyocytes. hERG, and IKr, are highly susceptible to block by a range of structurally diverse pharmacological agents. This property means that many drugs or potential drugs have the capacity to impair human ventricular repolarization, leading to drug-induced Long QT syndrome (LQTS). KCNE2 may also regulate hyperpolarization-activated, cyclic-nucleotide-gated (HCN) pacemaker channels in human heart and in the hearts of other species, as well as the Cav1.2 voltage-gated calcium channel.
In mice, mERG and KCNQ1, another Kv α subunit regulated by KCNE2, are neither influential nor highly expressed in adult ventricles. However, Kcne2-/- mice exhibit QT prolongation at baseline at 7 months of age, or earlier if provoked with a QT-prolonging agent such as sevoflurane. This is because KCNE2 is a promiscuous regulatory subunit that forms complexes with Kv1.5 and with Kv4.2 in adult mouse ventricular myocytes. KCNE2 increases currents though Kv4.2 channels and slows their inactivation. KCNE2 is required for Kv1.5 to localize to the intercalated discs of mouse ventricular myocytes. Kcne2 deletion in mice reduces the native currents generated in ventricular myocytes by Kv4.2 and Kv1.5, namely Ito and IKslow, respectively.
# Clinical Significance
## Gastric epithelium
Kcne2-/- mice exhibit achlorhydria, gastric hyperplasia, and mis-trafficking of KCNQ1 to the parietal cell basal membrane. The mis-trafficking occurs because KCNE3 is upregulated in the parietal cells of Kcne2-/- mice, and hijacks KCNQ1, taking it to the basolateral membrane. When both Kcne2 and Kcne3 are germline-deleted in mice, KCNQ1 traffics to the parietal cell apical membrane but the gastric phenotype is even worse than for Kcne2-/- mice, emphasizing that KCNQ1 requires KCNE2 co-assembly for functional attributes other than targeting in parietal cells. Kcne2-/- mice also develop gastritis cystica profunda and gastric neoplasia. Human KCNE2 downregulation is also observed in sites of gastritis cystica profunda and gastric adenocarcinoma.
## Thyroid epithelium
Positron emission tomography data show that with KCNE2, 124I uptake by the thyroid is impaired. Kcne2 deletion does not impair organification of iodide once it has been taken up by NIS. Pups raised by Kcne2-/- dams are particularly severely affected because rhey receive less milk (hypothyroidism of the dams impairs milk ejection), the milk they receive is deficient in T4, and they themselves cannot adequately transport iodide into the thyroid. Kcne2-/- pups exhibit stunted growth, alopecia, cardiomegaly and reduced cardiac ejection fraction, all of which are alleviated by thyroid hormone supplementation of pups or dams. Surrogating Kcne2-/- pups with Kcne2+/+ dams also alleviates these phenotypes, highlighting the influence of maternal genotype in this case.
## Heart
As observed for hERG mutations, KCNE2 loss-of-function mutations are associated with inherited LQTS, and hERG-KCNE2 channels carrying the mutations show reduced activity compared to wild-type channels. In addition, some KCNE2 mutations and also more common polymorphisms are associated with drug-induced LQTS. In several cases, specific KCNE2 sequence variants increase the susceptibility to hERG-KCNE2 channel inhibition by the drug that precipitated the QT prolongation in the patient from which the gene variant was isolated. LQTS predisposes to potentially lethal ventricular cardiac arrhythmias including torsades de pointe, which can degenerate into ventricular fibrillation and sudden cardiac death. Moreover, KCNE2 gene variation can disrupt HCN1-KCNE2 channel function and this may potentially contribute to cardiac arrhythmogenesis. KCNE2 is also associated with familial atrial fibrillation, which may involve excessive KCNQ1-KCNE2 current caused by KCNE2 gain-of-function mutations.
Recently, a battery of extracardiac effects were discovered in Kcne2-/- mice that may contribute to cardiac arrhythmogenesis in Kcne2-/- mice and could potentially contribute to human cardiac arrhythmias if similar effects are observed in human populations. Kcne2 deletion in mice causes anemia, glucose intolerance, dyslipidemia, hyperkalemia and elevated serum angiotensin II. Some or all of these might contribute to predisposition to sudden cardiac death in Kcne2-/- mice in the context of myocardial ischemia and post-ischemic arrhythmogenesis.
### Clinical Marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the KCNE2 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). | KCNE2
Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21.[1][2] MiRP1 is a voltage-gated potassium channel accessory subunit (beta subunit) associated with Long QT syndrome.[1] It is ubiquitously expressed in many tissues and cell types.[3] Because of this and its ability to regulate multiple different ion channels, KCNE2 exerts considerable influence on a number of cell types and tissues.[1][4] Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellular N-terminal and intracellular C-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias. The KCNE2 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[5] More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.
# Discovery
Steve Goldstein (then at Yale University) used a BLAST search strategy, focusing on KCNE1 sequence stretches known to be important for function, to identify related expressed sequence tags (ESTs) in the NCBI database. Using sequences from these ESTs, KCNE2, 3 and 4 were cloned.[1]
# Tissue distribution
KCNE2 protein is most readily detected in the choroid plexus epithelium, gastric parietal cells, and thyroid epithelial cells. KCNE2 is also expressed in atrial and ventricular cardiomyocytes, the pancreas, pituitary gland, and lung epithelium. In situ hybridization data suggest that KCNE2 transcript may also be expressed in various neuronal populations.[6]
# Structure
## Gene
The KCNE2 gene resides on chromosome 21 at the band 21q22.11 and contains 2 exons.[2] Since human KCNE2 is located ~79 kb from KCNE1 and in the opposite direction, KCNE2 is proposed to originate from a gene duplication event.[7]
## Protein
This protein belongs to the potassium channel KCNE family and is one five single transmembrane domain voltage-gated potassium (Kv) channel ancillary subunits.[8][9] KCNE2 is composed of three major domains: the N-terminal domain, the transmembrane domain, and the C-terminal domain. The N-terminal domain protrudes out of the extracellular side of the cell membrane and is, thus, soluble in the aqueous environment. Meanwhile, the transmembrane and C-terminal domains are lipid-soluble to enable the protein to incorporate into the cell membrane.[9] The C-terminal faces the intracellular side of the membrane and may share a putative PKC phosphorylation site with other KCNE proteins.
Like other KCNEs, KCNE2 forms a heteromeric complex with the Kv α subunits.[7]
# Function
## Choroid plexus epithelium
KCNE2 protein is most readily detected in the choroid plexus epithelium, at the apical side. KCNE2 forms complexes there with the voltage-gated potassium channel α subunit, Kv1.3. In addition, KCNE2 forms reciprocally regulating tripartite complexes in the choroid plexus epithelium with the KCNQ1 α subunit and the sodium-dependent myo-inositol transporter, SMIT1. Kcne2-/- mice exhibit increased seizure susceptibility, reduced immobility time in the tail suspension test, and reduced cerebrospinal fluid myo-inositol content, compared to wild-type littermates. Mega-dosing of myo-inositol reverses all these phenotypes, suggesting a link between myo-inositol and the seizure susceptibility and behavioral alterations in Kcne2-/- mice.[10][11]
## Gastric epithelium
KCNE2 is also highly expressed in parietal cells of the gastric epithelium, also at the apical side. In these cells, KCNQ1-KCNE2 K+ channels, which are constitutively active, provide a conduit to return K+ ions back to the stomach lumen. The K+ ions enter the parietal cell through the gastric H+/K+-ATPase, which swaps them for protons as it acidifies the stomach. While KCNQ1 channels are inhibited by low extracellular pH, KCNQ1-KCNE2 channels activity is augmented by extracellular protons, an ideal characteristic for their role in parietal cells.[12][13][14]
## Thyroid epithelium
KCNE2 forms constitutively active K+ channels with KCNQ1 in the basolateral membrane of thyroid epithelial cells. Kcne2-/- mice exhibit hypothyroidism, particularly apparent during gestation or lactation. KCNQ1-KCNE2 is required for optimal iodide uptake into the thyroid by the basolateral sodium iodide symporter (NIS). Iodide is required for biosynthesis of thyroid hormones.[15][16]
## Heart
KCNE2 was originally discovered to regulate hERG channel function. KCNE2 decreases marcoscopic and unitary current through hERG, and speeds hERG deactivation. hERG generates IKr, the most prominent repolarizing current in human ventricular cardiomyocytes. hERG, and IKr, are highly susceptible to block by a range of structurally diverse pharmacological agents. This property means that many drugs or potential drugs have the capacity to impair human ventricular repolarization, leading to drug-induced Long QT syndrome (LQTS).[1] KCNE2 may also regulate hyperpolarization-activated, cyclic-nucleotide-gated (HCN) pacemaker channels in human heart and in the hearts of other species, as well as the Cav1.2 voltage-gated calcium channel.[17][18]
In mice, mERG and KCNQ1, another Kv α subunit regulated by KCNE2, are neither influential nor highly expressed in adult ventricles. However, Kcne2-/- mice exhibit QT prolongation at baseline at 7 months of age, or earlier if provoked with a QT-prolonging agent such as sevoflurane. This is because KCNE2 is a promiscuous regulatory subunit that forms complexes with Kv1.5 and with Kv4.2 in adult mouse ventricular myocytes. KCNE2 increases currents though Kv4.2 channels and slows their inactivation. KCNE2 is required for Kv1.5 to localize to the intercalated discs of mouse ventricular myocytes. Kcne2 deletion in mice reduces the native currents generated in ventricular myocytes by Kv4.2 and Kv1.5, namely Ito and IKslow, respectively.[19]
# Clinical Significance
## Gastric epithelium
Kcne2-/- mice exhibit achlorhydria, gastric hyperplasia, and mis-trafficking of KCNQ1 to the parietal cell basal membrane. The mis-trafficking occurs because KCNE3 is upregulated in the parietal cells of Kcne2-/- mice, and hijacks KCNQ1, taking it to the basolateral membrane. When both Kcne2 and Kcne3 are germline-deleted in mice, KCNQ1 traffics to the parietal cell apical membrane but the gastric phenotype is even worse than for Kcne2-/- mice, emphasizing that KCNQ1 requires KCNE2 co-assembly for functional attributes other than targeting in parietal cells. Kcne2-/- mice also develop gastritis cystica profunda and gastric neoplasia. Human KCNE2 downregulation is also observed in sites of gastritis cystica profunda and gastric adenocarcinoma.[12][13][14]
## Thyroid epithelium
Positron emission tomography data show that with KCNE2, 124I uptake by the thyroid is impaired. Kcne2 deletion does not impair organification of iodide once it has been taken up by NIS. Pups raised by Kcne2-/- dams are particularly severely affected because rhey receive less milk (hypothyroidism of the dams impairs milk ejection), the milk they receive is deficient in T4, and they themselves cannot adequately transport iodide into the thyroid. Kcne2-/- pups exhibit stunted growth, alopecia, cardiomegaly and reduced cardiac ejection fraction, all of which are alleviated by thyroid hormone supplementation of pups or dams. Surrogating Kcne2-/- pups with Kcne2+/+ dams also alleviates these phenotypes, highlighting the influence of maternal genotype in this case.[15][16]
## Heart
As observed for hERG mutations, KCNE2 loss-of-function mutations are associated with inherited LQTS, and hERG-KCNE2 channels carrying the mutations show reduced activity compared to wild-type channels. In addition, some KCNE2 mutations and also more common polymorphisms are associated with drug-induced LQTS. In several cases, specific KCNE2 sequence variants increase the susceptibility to hERG-KCNE2 channel inhibition by the drug that precipitated the QT prolongation in the patient from which the gene variant was isolated.[1][20] LQTS predisposes to potentially lethal ventricular cardiac arrhythmias including torsades de pointe, which can degenerate into ventricular fibrillation and sudden cardiac death.[1] Moreover, KCNE2 gene variation can disrupt HCN1-KCNE2 channel function and this may potentially contribute to cardiac arrhythmogenesis.[17] KCNE2 is also associated with familial atrial fibrillation, which may involve excessive KCNQ1-KCNE2 current caused by KCNE2 gain-of-function mutations.[21]
[22]
Recently, a battery of extracardiac effects were discovered in Kcne2-/- mice that may contribute to cardiac arrhythmogenesis in Kcne2-/- mice and could potentially contribute to human cardiac arrhythmias if similar effects are observed in human populations. Kcne2 deletion in mice causes anemia, glucose intolerance, dyslipidemia, hyperkalemia and elevated serum angiotensin II. Some or all of these might contribute to predisposition to sudden cardiac death in Kcne2-/- mice in the context of myocardial ischemia and post-ischemic arrhythmogenesis.[23]
### Clinical Marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the KCNE2 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[5] | https://www.wikidoc.org/index.php/KCNE2 | |
0654ef53bf2295004cf5c68ced3505efbb766edb | wikidoc | KCNE3 | KCNE3
Potassium voltage-gated channel, Isk-related family, member 3 (KCNE3), also known as MinK-related peptide 2 (MiRP2) is a protein that in humans is encoded by the KCNE3 gene.
# Function
Voltage-gated potassium channels (Kv) represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. KCNE3 encodes a member of the five-strong KCNE family of voltage-gated potassium (Kv) channel ancillary or β subunits.
KCNE3 is best known for modulating the KCNQ1 Kv α subunit, but it also regulates hERG, Kv2.1, Kv3.x, Kv4.x and Kv12.2 in heterologous co-expression experiments and/or in vivo.
Co-assembly with KCNE3 converts KCNQ1 from a voltage-dependent delayed rectifier K+ channel to a constitutively open K+ channel with an almost linear current/voltage (I/V) relationship. KCNQ1-KCNE3 channels have been detected in the basolateral membrane of mouse small intestinal crypts, where they provide a driving force to regulate Cl- secretion. Specific amino acids within the transmembrane segment (V72) and extracellular domain (D54 and D55) of KCNE3 are important for its control of KCNQ1 voltage dependence. D54 and D55 interact electrostatically with R237 in the S4 segment of the KCNQ1 voltage sensor, helping to stabilize S4 in the activated state, which in turn locks open the channel unless the cell is held at a strongly hyperpolarizing (negative) membrane potential. The ability of KCNQ1-KCNE3 channels to remain open at weakly negative membrane potentials permits their activity in non-excitable, polarized epithelial cells such as those in the intestine.
KCNE3 also interacts with hERG, and when co-expressed in Xenopus laevis oocytes KCNE3 inhibits hERG activity by an unknown mechanism. It is not known whether hERG-KCNE3 complexes occur in vivo.
KCNE3 interacts with Kv2.1 in vitro and forms complexes with it in rat heart and brain. KCNE3 slows Kv2.1 activation and deactivation. KCNE3 can also regulate channels of the Kv3 subfamily, which are best known for permitting ultrarapid firing of neurons because of the extremely fast gating (activation and deactivation). KCNE3 moderately slows Kv3.1 and Kv3.2 activation and deactivation, and moderately speeds their C-type inactivation. It is possible that KCNE3 (and KCNE1 and 2) regulation of Kv3.1 and Kv3.2 helps to increase functional diversity within the Kv3 subfamily. KCNE3 also regulates Kv3.4, augments its current by increasing the unitary conductance and by left-shifting the voltage dependence such that the channel can open at more negative voltages. This may allow Kv3.4-KCNE3 channels to contribute to setting resting membrane potential.
KCNE3 inhibits the fast inactivating Kv channel Kv4.3, which generates the transient outward Kv current (Ito) in human cardiac myocytes). similarly, KCNE3 was recently found to inhibit Kv4.2, and it is thought that this regulation modulates spike frequency and other electrical properties of auditory neurons.
Kv12.2 channels were found to be inhibited by endogenous KCNE3 (and KCNE1) subunits in Xenopus laevis oocytes. Thus, silencing of endogenous KCNE3 or KCNE1 using siRNA increases the macroscopic current of exogenously expressed Kv12.2. Kv12.2 forms a tripartite complex with KCNE1 and KCNE3 in oocytes, and may do so in mouse brain. Previously, endogenous oocyte KCNE3 and KCNE1 were also found to inhibit exogenous hERG activity and slow the gating of exogenous Kv2.1.
# Structure
KCNE proteins are type I membrane proteins, and each assembles with one or more types of Kv channel α subunit to modulate their gating kinetics and other functional parameters. KCNE3 has a larger predicted extracellular domain, and smaller predicted intracellular domain, in terms of primary structure, when compared to other KCNE proteins. As with other KCNE proteins, the transmembrane segment of KCNE3 is thought to be α-helical, and the extracellular domain also adopts a partly helical structure. KCNE3, like KCNE1 and possibly other KCNE proteins, are thought to make contact with the S4 of one α subunit and the S6 of another α subunit within the tetramer of Kv α subunits in a complex. No studies have as yet reported the number of KCNE3 subunits within a functional channel complex; it is likely to be either 2 or 4.
# Tissue distribution
KCNE3 is most prominently expressed in the colon, small intestine, and specific cell types in the stomach. It is also detectable in the kidney and trachea, and depending on the species is also reportedly expressed at lower levels in the brain, heart and skeletal muscle. Specifically, KCNE3 was detected in rat, horse and human heart, but not in mouse heart. Some have observed KCNE3 expression in rat brain, rat and human skeletal muscle, and the mouse C2C12 skeletal muscle cell line, others have not detected it in these tissues in the mouse.
# Clinical significance
Genetic disruption of the Kcne3 gene in mice impairs intestinal cyclic AMP-stimulated chloride secretion via disruption of intestinal KCNQ1-KCNE3 channels that are important for regulating the chloride current. KCNE3 also performs a similar function in mouse tracheal epithelium. Kcne3 deletion in mice also predisposes to ventricular arrhythmogenesis, but KCNE3 expression is not detectable in mouse heart. The mechanism for ventricular arrhythmogenesis was demonstrated to be indirect, and associated with autoimmune attack of the adrenal gland and secondary hyperaldosteronism (KCNE3 is not detectable in the adrenal gland). The elevated serum aldosterone predisposes to arrhythmias triggered in a coronary artery ligation ischemia/reperfusion injury model. Blockade of the aldosterone receptor with spironolactone removed the ventricular arrhythmia predisposition in Kcne3-/- mice. Kcne3 deletion also impairs auditory function because of the loss of regulation of Kv4.2 channels by KCNE3 in spiral ganglion neurons (SGNs) of the auditory system. KCNE3 is thought to regulate SGN firing properties and membrane potential via its modulation of Kv4.2.
Mutations in human KCNE3 have been associated with hypokalemic periodic paralysis and Brugada syndrome.
The association with the R83H mutation in KCNE3 is controversial and other groups have detected the same mutation in individuals not exhibiting symptoms of periodic paralysis. The mutation may instead be a benign polymorphism, or else it requires another genetic or environmental 'hit' before it becomes pathogenic. Kv channels formed by Kv3.4 and R83H-KCNE3 have impaired function compared to wild-type channels, are less able to open at negative potentials and are sensitive to proton block during acidosis.
KCNE3-linked Brugada syndrome is thought to arise because of mutant KCNE3 being unable to inhibit Kv4.3 channels in ventricular myocytes as it is suggested to do in healthy individuals. It appears that, unlike in mice, KCNE3 expression is detectable in human heart. It has not been reported whether people with KCNE3 mutations also have adrenal gland-related symptoms such as hyperaldosteronism.
KCNE3 mutations have been suggested to associate with Ménière’s disease in Japanese, a condition that presents as tinnitus, spontaneous vertigo, and periodic hearing loss, however this association is also controversial and was not observed in a Caucasian population. In a study of tinnitus utilizing deep resequencing analysis, the authors were not able to prove or disprove association of KCNE3 sequence variation with tinnitus. | KCNE3
Potassium voltage-gated channel, Isk-related family, member 3 (KCNE3), also known as MinK-related peptide 2 (MiRP2) is a protein that in humans is encoded by the KCNE3 gene.[1][2]
# Function
Voltage-gated potassium channels (Kv) represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. KCNE3 encodes a member of the five-strong KCNE family of voltage-gated potassium (Kv) channel ancillary or β subunits.
KCNE3 is best known for modulating the KCNQ1 Kv α subunit, but it also regulates hERG, Kv2.1, Kv3.x, Kv4.x and Kv12.2 in heterologous co-expression experiments and/or in vivo.
Co-assembly with KCNE3 converts KCNQ1 from a voltage-dependent delayed rectifier K+ channel to a constitutively open K+ channel with an almost linear current/voltage (I/V) relationship.[3] KCNQ1-KCNE3 channels have been detected in the basolateral membrane of mouse small intestinal crypts, where they provide a driving force to regulate Cl- secretion.[4] Specific amino acids within the transmembrane segment (V72) and extracellular domain (D54 and D55) of KCNE3 are important for its control of KCNQ1 voltage dependence.[5][6] D54 and D55 interact electrostatically with R237 in the S4 segment of the KCNQ1 voltage sensor, helping to stabilize S4 in the activated state, which in turn locks open the channel unless the cell is held at a strongly hyperpolarizing (negative) membrane potential. The ability of KCNQ1-KCNE3 channels to remain open at weakly negative membrane potentials permits their activity in non-excitable, polarized epithelial cells such as those in the intestine.
KCNE3 also interacts with hERG, and when co-expressed in Xenopus laevis oocytes KCNE3 inhibits hERG activity by an unknown mechanism. It is not known whether hERG-KCNE3 complexes occur in vivo.[3]
KCNE3 interacts with Kv2.1 in vitro and forms complexes with it in rat heart and brain. KCNE3 slows Kv2.1 activation and deactivation. KCNE3 can also regulate channels of the Kv3 subfamily, which are best known for permitting ultrarapid firing of neurons because of the extremely fast gating (activation and deactivation). KCNE3 moderately slows Kv3.1 and Kv3.2 activation and deactivation, and moderately speeds their C-type inactivation.[7][8] It is possible that KCNE3 (and KCNE1 and 2) regulation of Kv3.1 and Kv3.2 helps to increase functional diversity within the Kv3 subfamily.[9] KCNE3 also regulates Kv3.4, augments its current by increasing the unitary conductance and by left-shifting the voltage dependence such that the channel can open at more negative voltages. This may allow Kv3.4-KCNE3 channels to contribute to setting resting membrane potential.[10]
KCNE3 inhibits the fast inactivating Kv channel Kv4.3, which generates the transient outward Kv current (Ito) in human cardiac myocytes).[11] similarly, KCNE3 was recently found to inhibit Kv4.2, and it is thought that this regulation modulates spike frequency and other electrical properties of auditory neurons.[12]
Kv12.2 channels were found to be inhibited by endogenous KCNE3 (and KCNE1) subunits in Xenopus laevis oocytes. Thus, silencing of endogenous KCNE3 or KCNE1 using siRNA increases the macroscopic current of exogenously expressed Kv12.2. Kv12.2 forms a tripartite complex with KCNE1 and KCNE3 in oocytes, and may do so in mouse brain.[13] Previously, endogenous oocyte KCNE3 and KCNE1 were also found to inhibit exogenous hERG activity and slow the gating of exogenous Kv2.1.[14][15]
# Structure
KCNE proteins are type I membrane proteins, and each assembles with one or more types of Kv channel α subunit to modulate their gating kinetics and other functional parameters. KCNE3 has a larger predicted extracellular domain, and smaller predicted intracellular domain, in terms of primary structure, when compared to other KCNE proteins.[16] As with other KCNE proteins, the transmembrane segment of KCNE3 is thought to be α-helical, and the extracellular domain also adopts a partly helical structure.[17] KCNE3, like KCNE1 and possibly other KCNE proteins, are thought to make contact with the S4 of one α subunit and the S6 of another α subunit within the tetramer of Kv α subunits in a complex. No studies have as yet reported the number of KCNE3 subunits within a functional channel complex; it is likely to be either 2 or 4.
# Tissue distribution
KCNE3 is most prominently expressed in the colon, small intestine, and specific cell types in the stomach.[18] It is also detectable in the kidney and trachea, and depending on the species is also reportedly expressed at lower levels in the brain, heart and skeletal muscle. Specifically, KCNE3 was detected in rat, horse and human heart,[8][19][20] but not in mouse heart.[4][21] Some have observed KCNE3 expression in rat brain, rat and human skeletal muscle, and the mouse C2C12 skeletal muscle cell line, others have not detected it in these tissues in the mouse.[4][7][10][22]
# Clinical significance
Genetic disruption of the Kcne3 gene in mice impairs intestinal cyclic AMP-stimulated chloride secretion via disruption of intestinal KCNQ1-KCNE3 channels that are important for regulating the chloride current. KCNE3 also performs a similar function in mouse tracheal epithelium. Kcne3 deletion in mice also predisposes to ventricular arrhythmogenesis, but KCNE3 expression is not detectable in mouse heart. The mechanism for ventricular arrhythmogenesis was demonstrated to be indirect, and associated with autoimmune attack of the adrenal gland and secondary hyperaldosteronism (KCNE3 is not detectable in the adrenal gland). The elevated serum aldosterone predisposes to arrhythmias triggered in a coronary artery ligation ischemia/reperfusion injury model. Blockade of the aldosterone receptor with spironolactone removed the ventricular arrhythmia predisposition in Kcne3-/- mice. Kcne3 deletion also impairs auditory function because of the loss of regulation of Kv4.2 channels by KCNE3 in spiral ganglion neurons (SGNs) of the auditory system. KCNE3 is thought to regulate SGN firing properties and membrane potential via its modulation of Kv4.2.[12]
Mutations in human KCNE3 have been associated with hypokalemic periodic paralysis[1] and Brugada syndrome.[23]
The association with the R83H mutation in KCNE3 is controversial and other groups have detected the same mutation in individuals not exhibiting symptoms of periodic paralysis.[24] The mutation may instead be a benign polymorphism, or else it requires another genetic or environmental 'hit' before it becomes pathogenic. Kv channels formed by Kv3.4 and R83H-KCNE3 have impaired function compared to wild-type channels, are less able to open at negative potentials and are sensitive to proton block during acidosis.[10][25]
KCNE3-linked Brugada syndrome is thought to arise because of mutant KCNE3 being unable to inhibit Kv4.3 channels in ventricular myocytes as it is suggested to do in healthy individuals. It appears that, unlike in mice, KCNE3 expression is detectable in human heart. It has not been reported whether people with KCNE3 mutations also have adrenal gland-related symptoms such as hyperaldosteronism.
KCNE3 mutations have been suggested to associate with Ménière’s disease in Japanese, a condition that presents as tinnitus, spontaneous vertigo, and periodic hearing loss,[26] however this association is also controversial and was not observed in a Caucasian population.[27] In a study of tinnitus utilizing deep resequencing analysis, the authors were not able to prove or disprove association of KCNE3 sequence variation with tinnitus.[28] | https://www.wikidoc.org/index.php/KCNE3 | |
a8c18077f9b6f3190aa7f80e965d6ed8d80b0644 | wikidoc | KCNE4 | KCNE4
Potassium voltage-gated channel subfamily E member 4, originally named MinK-related peptide 3 or MiRP3 when it was discovered, is a protein that in humans is encoded by the KCNE4 gene.
# Function
Voltage-gated potassium channels (Kv) represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. The KCNE4 gene encodes KCNE4 (originally named MinK-related peptide 3 or MiRP3), a member of the KCNE family of voltage-gated potassium (Kv) channel ancillary or β subunits.
KCNE4 is best known for modulating the KCNQ1 Kv α subunit, but it also regulates KCNQ4, Kv1.x, Kv2.1, Kv4.x and BK α subunits in heterologous co-expression experiments and/or in vivo. KCNE4 often, but not always, acts as an inhibitory subunit to suppress potassium channel function, but this varies depending on the channel subtype.
KCNE4 strongly inhibits the KCNQ1 potassium channel, which is known to play important roles in human cardiac myocyte repolarization, and in multiple epithelial cell types. KCNE4 inhibition of KCNQ1 requires calmodulin, which binds to both KCNQ1 and KCNE4. KCNE4 can also inhibit complexes formed by KCNQ1 and KCNE1. KCNE4 has no known effect on KCNQ2, KCNQ3 or KCNQ5 channels, but augments activity of KCNQ4 in HEK cells, mesenteric artery and Xenopus laevis oocytes.
KCNE4 strongly inhibits Kv1.1 and Kv1.3 channels when co-expressed in HEK cells and in Xenopus laevis oocytes, while leaving Kv1.2 and Kv1.4 currents unaffected. KCNE4 augments Kv1.5 current and surface expression twofold in CHO cells (but had no effect in Xenopus oocytes). Kcne4 deletion from mice impaired currents attributable to Kv1.5, in ventricular myocytes.
KCNE4 inhibited Kv2.1 currents by 90% but had little to no effect on currents generated by heteromers of Kv2.1 with the regulatory α subunit Kv6.4.
KCNE4 slows activation and inactivation of Kv4.2 channels, and induces overshoot upon recovery from inactivation. Co-expression with KChIP2 produces intermediate gating kinetics in complexes with Kv4.2 and KCNE4. Deletion of Kcne4 in mice impaired ventricular myocyte Ito, a current generated at least in part by Kv4.2.
Although mouse KCNE4 reportedly had no effect on Kv4.3 when coexpressed in oocytes, human KCNE4 was found to accelerate inactivation and recovery from inactivation of Kv4.3-KChIP2 complexes.
KCNE4 has also been found to regulate the large-conductance Ca2+-activated potassium channel, BK. KCNE4 inhibits BK activity by positive-shifting the voltage dependence of BK activation and accelerating BK protein degradation.
# Structure
KCNE4 is a type 1 membrane protein, with the transmembrane segment predicted to be alpha-helical. No studies have as yet reported the number of KCNE4 subunits within a functional channel complex; it is likely to be either 2 or 4. The majority of studies of KCNE4 function, structure-function relationships and effects of pathological gene sequence variants within KCNE4 have utilized the widely reported 170 residue version of the protein encoded by exon 2 of the human KCNE4 gene. However, in 2016 a longer form of the KCNE4 protein, termed KCNE4L, was discovered. An additional N-terminal portion of 51 residues, encoded by exon 1 of the human KCNE4 gene, were found to also be expressed in multiple human tissues, extending the human protein to 221 residues, by far the longest of the KCNE subunits. Human KCNE4L exhibits some functional differences to the shorter 170 residue form now also termed KCNE4S. KCNE4L is predicted to also be expressed in other mammals, reptiles, amphibians and fish, although the house mouse (Mus musculus) appears to only express KCNE4S because the KCNE4L start site is lacking in the house mouse genome.
# Tissue distribution
Human KCNE4L transcripts are most highly expressed in uterus, and next most highly expressed in atria, adrenal gland, lymph nodes, pituitary gland, spleen and ureter. KCNE4L transcript is also detectable in cervix, colon, optic nerve, ovary, oviduct, pancreas, skin, retina, spinal cord, stomach, thymus, and vagina.
In the rat heart, KCNE4 protein co-localizes with Kv4.2, a channel that KCNE4 also functionally regulates. In mouse heart, KCNE4 is preferentially expressed in ventricles versus atria, and in young adult males much more than young adult females. This is because cardiac KCNE4 expression is positively regulated by dihydrotestosterone. In rat mesenteric artery, KCNE4 augments KCNQ4 channel activity to regulate arterial tone.
# Clinical significance
A single polymorphism in the KCNE4 intracellular N-terminal domain, E145D, has been reported to affect predisposition to the relatively common chronic cardiac arrhythmia, atrial fibrillation, in Chinese populations, and to impair the ability of KCNE4 to inhibit KCNQ1. If KCNE4 inhibits KCNQ1 in the atrium, it is conceivable that removing this inhibition could shorten the atrial effective refractory period, which could predispose to atrial fibrillation, but this mechanism has not yet been substantiated with in vivo data. | KCNE4
Potassium voltage-gated channel subfamily E member 4, originally named MinK-related peptide 3 or MiRP3 when it was discovered, is a protein that in humans is encoded by the KCNE4 gene.[1][2]
# Function
Voltage-gated potassium channels (Kv) represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. The KCNE4 gene encodes KCNE4 (originally named MinK-related peptide 3 or MiRP3), a member of the KCNE family of voltage-gated potassium (Kv) channel ancillary or β subunits.[3]
KCNE4 is best known for modulating the KCNQ1 Kv α subunit, but it also regulates KCNQ4, Kv1.x, Kv2.1, Kv4.x and BK α subunits in heterologous co-expression experiments and/or in vivo. KCNE4 often, but not always, acts as an inhibitory subunit to suppress potassium channel function, but this varies depending on the channel subtype.
KCNE4 strongly inhibits the KCNQ1 potassium channel, which is known to play important roles in human cardiac myocyte repolarization, and in multiple epithelial cell types.[4] KCNE4 inhibition of KCNQ1 requires calmodulin, which binds to both KCNQ1 and KCNE4.[5] KCNE4 can also inhibit complexes formed by KCNQ1 and KCNE1.[6] KCNE4 has no known effect on KCNQ2, KCNQ3 or KCNQ5 channels, but augments activity of KCNQ4 in HEK cells, mesenteric artery[7] and Xenopus laevis oocytes.[8]
KCNE4 strongly inhibits Kv1.1 and Kv1.3 channels when co-expressed in HEK cells and in Xenopus laevis oocytes, while leaving Kv1.2 and Kv1.4 currents unaffected.[9] KCNE4 augments Kv1.5 current and surface expression twofold in CHO cells (but had no effect in Xenopus oocytes). Kcne4 deletion from mice impaired currents attributable to Kv1.5, in ventricular myocytes.[10]
KCNE4 inhibited Kv2.1 currents by 90% but had little to no effect on currents generated by heteromers of Kv2.1 with the regulatory α subunit Kv6.4.[11]
KCNE4 slows activation and inactivation of Kv4.2 channels, and induces overshoot upon recovery from inactivation. Co-expression with KChIP2 produces intermediate gating kinetics in complexes with Kv4.2 and KCNE4.[12] Deletion of Kcne4 in mice impaired ventricular myocyte Ito, a current generated at least in part by Kv4.2.[10]
Although mouse KCNE4 reportedly had no effect on Kv4.3 when coexpressed in oocytes,[9] human KCNE4 was found to accelerate inactivation and recovery from inactivation of Kv4.3-KChIP2 complexes.[13]
KCNE4 has also been found to regulate the large-conductance Ca2+-activated potassium channel, BK. KCNE4 inhibits BK activity by positive-shifting the voltage dependence of BK activation and accelerating BK protein degradation.[14]
# Structure
KCNE4 is a type 1 membrane protein, with the transmembrane segment predicted to be alpha-helical. No studies have as yet reported the number of KCNE4 subunits within a functional channel complex; it is likely to be either 2 or 4. The majority of studies of KCNE4 function, structure-function relationships and effects of pathological gene sequence variants within KCNE4 have utilized the widely reported 170 residue version of the protein encoded by exon 2 of the human KCNE4 gene. However, in 2016 a longer form of the KCNE4 protein, termed KCNE4L, was discovered. An additional N-terminal portion of 51 residues, encoded by exon 1 of the human KCNE4 gene, were found to also be expressed in multiple human tissues, extending the human protein to 221 residues, by far the longest of the KCNE subunits. Human KCNE4L exhibits some functional differences to the shorter 170 residue form now also termed KCNE4S. KCNE4L is predicted to also be expressed in other mammals, reptiles, amphibians and fish, although the house mouse (Mus musculus) appears to only express KCNE4S because the KCNE4L start site is lacking in the house mouse genome.[15]
# Tissue distribution
Human KCNE4L transcripts are most highly expressed in uterus, and next most highly expressed in atria, adrenal gland, lymph nodes, pituitary gland, spleen and ureter. KCNE4L transcript is also detectable in cervix, colon, optic nerve, ovary, oviduct, pancreas, skin, retina, spinal cord, stomach, thymus, and vagina.[15]
In the rat heart, KCNE4 protein co-localizes with Kv4.2, a channel that KCNE4 also functionally regulates.[16] In mouse heart, KCNE4 is preferentially expressed in ventricles versus atria, and in young adult males much more than young adult females. This is because cardiac KCNE4 expression is positively regulated by dihydrotestosterone.[10] In rat mesenteric artery, KCNE4 augments KCNQ4 channel activity to regulate arterial tone.[17]
# Clinical significance
A single polymorphism in the KCNE4 intracellular N-terminal domain, E145D, has been reported to affect predisposition to the relatively common chronic cardiac arrhythmia, atrial fibrillation, in Chinese populations,[18] and to impair the ability of KCNE4 to inhibit KCNQ1.[19] If KCNE4 inhibits KCNQ1 in the atrium, it is conceivable that removing this inhibition could shorten the atrial effective refractory period, which could predispose to atrial fibrillation, but this mechanism has not yet been substantiated with in vivo data. | https://www.wikidoc.org/index.php/KCNE4 | |
e2f6d4d5b664567a7192a5e300471dd510acbdb4 | wikidoc | KCNE5 | KCNE5
KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.
# Function
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. KCNE5 encodes a membrane protein, KCNE5 (originally named KCNE1-L) that has sequence similarity to the KCNE1 gene product, a member of the potassium channel, voltage-gated, isk-related subfamily.
The KCNE gene family comprises five genes in the human genome, each encoding a type I membrane protein. The KCNE subunits are potassium channel regulatory subunits that do not pass currents themselves but alter the properties of potassium channel pore-forming alpha subunits. KCNE5 is thus far the least-studied member of the KCNE family, but it is known to regulate a number of different Kv channel subtypes. KCNE5 co-assembles with KCNQ1, a Kv alpha subunit best known for its role in ventricular repolarization and in multiple epithelia. This co-assembly induces a +140 mV shift in voltage dependence of activation (when co-expressed in CHO cells) which would inhibit KCNQ1 activity across the normal physiological voltage range in most tissues.
KCNE5 also inhibits activity of channels formed with KCNQ1 and KCNE1. While reportedly not affecting KCNQ2, KCNQ2/3 or KCNQ5 channel activity, KCNE5 inhibits KCNQ4 in CHO cells but not in oocytes.
Although it has no known effects on hERG (Kv11.1) or Kv1.x family channel activity, KCNE5 inhibits Kv2.1 activity 50% and accelerates activation, slows deactivation and accelerates the recovery from closed state inactivation of channels formed by Kv2.1 and the 'silent' alpha subunit, Kv6.4.
KCNE5 was previously reported to not regulate Kv4.2 or Kv4.3, but has been found to accelerate, and left-shift the voltage dependence of, inactivation of Kv4.3-KChIP2 channel complexes.
# Structure
The KCNE family subunits are type I membrane proteins with an extracellular N-terminus and intracellular C-terminus. The transmembrane domain is alpha helical in KCNE1, 2 and 3 and predicted to also be helical in KCNE4 and KCNE5. The acknowledged role of members of the KCNE family is as Kv channel beta subunits, regulating the functional properties of Kv alpha subunits, with all three segments of the beta subunit contributing to binding, functional modulation and/or trafficking modulation to a greater or lesser degree. The high resolution structure of KCNE5 has not yet been determined, as of 2016. KCNE5 is an X-linked gene encoding a 143 residue protein in Homo sapiens.
# Tissue distribution
Human KCNE5 transcripts are most highly expressed in cardiac and skeletal muscle, spinal cord and brain, and it is also detectable in placenta. In mice, Kcne5 transcript was detected in embryonic cranial nerve migrating crest cells, ganglia, somites and myoepicaridal layer.
# Clinical significance
This intronless gene is deleted in AMME contiguous gene syndrome and is potentially involved in the cardiac and neurologic abnormalities found in the AMME contiguous gene syndrome.
KCNE5 is expressed in the human placenta and its expression increases in preeclampsia, although causality has not been established for this phenomenon.
Inherited sequence variants in human KCNE5 are associated with atrial fibrillation and Brugada syndrome. Atrial fibrillation is the most common chronic cardiac arrhythmia, affecting 2-3 million in the United States alone, predominantly in the aging population. A minority of cases are linked to ion channel gene mutations, whereas the majority are associated with structural heart defects. Brugada syndrome is a relatively rare but lethal ventricular arrhythmia most commonly linked to voltage-gated sodium channel gene SCN5A mutations, but also associated with some Kv channel gene sequence variants.
KCNE5 mutation L65F is associated with atrial fibrillation and upregulates KCNQ1-KCNE1 currents when co-expressed with these subunits. In contrast, a polymorphism in KCNE5 encoding a P33S substitution was found to be less common in atrial fibrillation patients than in control subjects, although these findings were at odds with those of other studies.
KCNE5-Y81H was detected in a man with a type 1 Brugada pattern body-surface electrocardiogram, while KCNE5-D92E:E93X was detected in another case of Brugada and associated with premature sudden death in other male family members, but not females - significant because KCNE5 is an X-linked gene. These two gene variants did not affect KCNQ1-KCNE1 currents when co-expressed in CHO cells, but produced larger currents than wild-type KCNE5 when coexpressed with Kv4.3-KChIP2, giving a possible mechanism for Brugada syndrome, i.e., increased ventricular Ito density.
A KCNE5 non-coding region gene variant, the G variant of the rs697829 A/G polymorphism, has also been reported to associate with prolonged QT interval and higher hazard ratio for death, compared to the G variant.
# Notes | KCNE5
KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.[1][2]
# Function
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. KCNE5 encodes a membrane protein, KCNE5 (originally named KCNE1-L) that has sequence similarity to the KCNE1 gene product, a member of the potassium channel, voltage-gated, isk-related subfamily.[2]
The KCNE gene family comprises five genes in the human genome, each encoding a type I membrane protein. The KCNE subunits are potassium channel regulatory subunits that do not pass currents themselves but alter the properties of potassium channel pore-forming alpha subunits. KCNE5 is thus far the least-studied member of the KCNE family, but it is known to regulate a number of different Kv channel subtypes. KCNE5 co-assembles with KCNQ1, a Kv alpha subunit best known for its role in ventricular repolarization and in multiple epithelia. This co-assembly induces a +140 mV shift in voltage dependence of activation (when co-expressed in CHO cells) which would inhibit KCNQ1 activity across the normal physiological voltage range in most tissues.[3]
KCNE5 also inhibits activity of channels formed with KCNQ1 and KCNE1.[4] While reportedly not affecting KCNQ2, KCNQ2/3 or KCNQ5 channel activity, KCNE5 inhibits KCNQ4 in CHO cells[3] but not in oocytes.[5]
Although it has no known effects on hERG (Kv11.1) or Kv1.x family channel activity, KCNE5 inhibits Kv2.1 activity 50% and accelerates activation, slows deactivation and accelerates the recovery from closed state inactivation of channels formed by Kv2.1 and the 'silent' alpha subunit, Kv6.4.[6]
KCNE5 was previously reported to not regulate Kv4.2 or Kv4.3, but has been found to accelerate, and left-shift the voltage dependence of, inactivation of Kv4.3-KChIP2 channel complexes.[7]
# Structure
The KCNE family subunits are type I membrane proteins with an extracellular N-terminus and intracellular C-terminus.[8] The transmembrane domain is alpha helical in KCNE1, 2 and 3 and predicted to also be helical in KCNE4 and KCNE5. The acknowledged role of members of the KCNE family is as Kv channel beta subunits, regulating the functional properties of Kv alpha subunits, with all three segments of the beta subunit contributing to binding, functional modulation and/or trafficking modulation to a greater or lesser degree. The high resolution structure of KCNE5 has not yet been determined, as of 2016. KCNE5 is an X-linked gene encoding a 143 residue protein in Homo sapiens.[1]
# Tissue distribution
Human KCNE5 transcripts are most highly expressed in cardiac and skeletal muscle, spinal cord and brain, and it is also detectable in placenta.[1][9] In mice, Kcne5 transcript was detected in embryonic cranial nerve migrating crest cells, ganglia, somites and myoepicaridal layer.[1]
# Clinical significance
This intronless gene is deleted in AMME contiguous gene syndrome and is potentially involved in the cardiac and neurologic abnormalities found in the AMME contiguous gene syndrome.[1]
KCNE5 is expressed in the human placenta and its expression increases in preeclampsia, although causality has not been established for this phenomenon.[9]
Inherited sequence variants in human KCNE5 are associated with atrial fibrillation and Brugada syndrome. Atrial fibrillation is the most common chronic cardiac arrhythmia, affecting 2-3 million in the United States alone, predominantly in the aging population. A minority of cases are linked to ion channel gene mutations, whereas the majority are associated with structural heart defects. Brugada syndrome is a relatively rare but lethal ventricular arrhythmia most commonly linked to voltage-gated sodium channel gene SCN5A mutations, but also associated with some Kv channel gene sequence variants.
KCNE5 mutation L65F is associated with atrial fibrillation and upregulates KCNQ1-KCNE1 currents when co-expressed with these subunits. In contrast, a polymorphism in KCNE5 encoding a P33S substitution was found to be less common in atrial fibrillation patients than in control subjects,[10] although these findings were at odds with those of other studies.[11]
KCNE5-Y81H was detected in a man with a type 1 Brugada pattern body-surface electrocardiogram, while KCNE5-D92E:E93X was detected in another case of Brugada and associated with premature sudden death in other male family members, but not females - significant because KCNE5 is an X-linked gene. These two gene variants did not affect KCNQ1-KCNE1 currents when co-expressed in CHO cells, but produced larger currents than wild-type KCNE5 when coexpressed with Kv4.3-KChIP2, giving a possible mechanism for Brugada syndrome, i.e., increased ventricular Ito density.[12]
A KCNE5 non-coding region gene variant, the G variant of the rs697829 A/G polymorphism, has also been reported to associate with prolonged QT interval and higher hazard ratio for death, compared to the G variant.[13]
# Notes | https://www.wikidoc.org/index.php/KCNE5 | |
cde95bbefd67d12af6c1fb545c2a68c62d739379 | wikidoc | KCNH1 | KCNH1
Potassium voltage-gated channel subfamily H member 1 is a protein that in humans is encoded by the KCNH1 gene.
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms.
# Interactions
KCNH1 has been shown to interact with KCNB1.
# Pathologies
A recent study has shown that de novo missense mutations in the KCNH1 gene results in deleterious gain of function, resulting in a multisystem developmental disorder known as Temple-Baraitser syndrome (TBS). TBS is categorized by intellectual disabilities, epilepsy, and aplasia of the nails. Simons et al. suggested that mutational mosaicism present in the mothers of some probands was responsible for their children's TBS phenotype. This is further evidence of the role that genetic mosaicism plays in the etiology of neurological disorders. | KCNH1
Potassium voltage-gated channel subfamily H member 1 is a protein that in humans is encoded by the KCNH1 gene.[1][2][3]
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms.[3]
# Interactions
KCNH1 has been shown to interact with KCNB1.[4]
# Pathologies
A recent study has shown that de novo missense mutations in the KCNH1 gene results in deleterious gain of function, resulting in a multisystem developmental disorder known as Temple-Baraitser syndrome (TBS). TBS is categorized by intellectual disabilities, epilepsy, and aplasia of the nails. Simons et al. suggested that mutational mosaicism present in the mothers of some probands was responsible for their children's TBS phenotype. This is further evidence of the role that genetic mosaicism plays in the etiology of neurological disorders.[5] | https://www.wikidoc.org/index.php/KCNH1 | |
fb8420d887a68f59325dd08150899d460d9d1e29 | wikidoc | KCNH5 | KCNH5
Potassium voltage-gated channel, subfamily H (eag-related), member 5, also known as KCNH5, is a human gene encoding the Kv10.2 protein.
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. This gene is not expressed in differentiating myoblasts. Alternative splicing results in three transcript variants encoding distinct isoforms.
Mutations in this gene have been linked to cases of early onset Epilepsy.(10.1111/epi.12201) | KCNH5
Potassium voltage-gated channel, subfamily H (eag-related), member 5, also known as KCNH5, is a human gene encoding the Kv10.2 protein.[1]
Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. This gene is not expressed in differentiating myoblasts. Alternative splicing results in three transcript variants encoding distinct isoforms.[1]
Mutations in this gene have been linked to cases of early onset Epilepsy.(10.1111/epi.12201) | https://www.wikidoc.org/index.php/KCNH5 | |
79529b33b99eae81e8e17aa9ceaad6dc7bd4335a | wikidoc | KCNJ5 | KCNJ5
G protein-activated inward rectifier potassium channel 4 is a protein that in humans is encoded by the KCNJ5 gene and is a type of G protein-gated ion channel.
# Function
Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins. It may associate with other G-protein-activated potassium channel subunits to form a heterotetrameric pore-forming complex.
In humans KCNJ5 is mainly expressed in adrenal gland and pituitary, although it is also detected at low levels in pancreas, spleen, lung, heart and brain . Consistent with this expression pattern, mutations in KCNJ5/Kir3.4 can cause familial hyperaldosteronism type III and a type of long QT syndrome.
# Interactions
KCNJ5 has been shown to interact with KCNJ3. | KCNJ5
G protein-activated inward rectifier potassium channel 4 is a protein that in humans is encoded by the KCNJ5 gene and is a type of G protein-gated ion channel.[1][2]
# Function
Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, is controlled by G-proteins. It may associate with other G-protein-activated potassium channel subunits to form a heterotetrameric pore-forming complex.[2]
In humans KCNJ5 is mainly expressed in adrenal gland and pituitary, although it is also detected at low levels in pancreas, spleen, lung, heart and brain [3]. Consistent with this expression pattern, mutations in KCNJ5/Kir3.4 can cause familial hyperaldosteronism type III and a type of long QT syndrome.[4]
# Interactions
KCNJ5 has been shown to interact with KCNJ3.[5][6] | https://www.wikidoc.org/index.php/KCNJ5 | |
47f4b16be7b0c41f5aeb7a2876a34e8a8840ef11 | wikidoc | KCNK2 | KCNK2
Potassium channel subfamily K member 2 is a protein that in humans is encoded by the KCNK2 gene.
This gene encodes K2P2.1, one of the members of the two-pore-domain background potassium channel protein family. This type of potassium channel is formed by two homodimers that create a channel that leaks potassium out of the cell to control resting membrane potential. The channel can be opened, however, by certain anesthetics, membrane stretching, intracellular acidosis, and heat. Three transcript variants encoding different isoforms have been found for this gene.
# Function in neurons
Another name for this channel is TREK-1. TREK-1 is part of the subfamily of mechano-gated potassium channels that are present in mammalian neurons. They can be gated in both chemical and physical ways and can be opened via both physical stimuli and chemical stimuli. TREK-1 channels are found in a variety of tissues, but are particularly abundant in the brain and heart and are seen in various types of neurons. The C-terminal of TREK-1 channels plays a role in the mechanosensitivity of the channels.
In the neurons of the central nervous system, TREK-1 channels are important in physiological, pathophysiological, and pharmacological processes, including having a role in electrogenesis, ischemia, and anesthesia. TREK-1 has an important role in neuroprotection against epilepsy and brain and spinal cord ischemia and is being evaluated as a potential target for new developments of therapeutic agents for neurology and anesthesiology.
In the absence of a properly functioning cytoskeleton, TREK-1 channels can still open via mechanical gating. The cell membrane functions independently of the cytoskeleton and the thickness and curvature of the membrane is able to modulate the activity of the TREK-1 channels. The insertion of certain compounds into the membrane is thought to mediate the opening of TREK-1 by forming a curve in the membrane. | KCNK2
Potassium channel subfamily K member 2 is a protein that in humans is encoded by the KCNK2 gene.[1][2][3]
This gene encodes K2P2.1, one of the members of the two-pore-domain background potassium channel protein family. This type of potassium channel is formed by two homodimers that create a channel that leaks potassium out of the cell to control resting membrane potential. The channel can be opened, however, by certain anesthetics, membrane stretching, intracellular acidosis, and heat. Three transcript variants encoding different isoforms have been found for this gene.[3]
# Function in neurons
Another name for this channel is TREK-1. TREK-1 is part of the subfamily of mechano-gated potassium channels that are present in mammalian neurons. They can be gated in both chemical and physical ways and can be opened via both physical stimuli and chemical stimuli. TREK-1 channels are found in a variety of tissues, but are particularly abundant in the brain and heart and are seen in various types of neurons.[4] The C-terminal of TREK-1 channels plays a role in the mechanosensitivity of the channels.[5]
In the neurons of the central nervous system, TREK-1 channels are important in physiological, pathophysiological, and pharmacological processes, including having a role in electrogenesis, ischemia, and anesthesia. TREK-1 has an important role in neuroprotection against epilepsy and brain and spinal cord ischemia and is being evaluated as a potential target for new developments of therapeutic agents for neurology and anesthesiology.[6]
In the absence of a properly functioning cytoskeleton, TREK-1 channels can still open via mechanical gating.[5] The cell membrane functions independently of the cytoskeleton and the thickness and curvature of the membrane is able to modulate the activity of the TREK-1 channels.[7] The insertion of certain compounds into the membrane is thought to mediate the opening of TREK-1 by forming a curve in the membrane.[5] | https://www.wikidoc.org/index.php/KCNK2 | |
1d7a2febbec00ff6e84cdef0dd096edbfceac6b5 | wikidoc | KCNK3 | KCNK3
Potassium channel subfamily K member 3 is a protein that in humans is encoded by the KCNK3 gene.
This gene encodes K2P3.1, one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. K2P3.1 is an outwardly rectifying channel that is sensitive to changes in extracellular pH and is inhibited by extracellular acidification. Also referred to as an acid-sensitive potassium channel, it is activated by the anesthetics halothane and isoflurane. Although three transcripts are detected in northern blots, there is currently no sequence available to confirm transcript variants for this gene.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
# Interactions
KCNK3 has been shown to interact with YWHAB and S100A10. | KCNK3
Potassium channel subfamily K member 3 is a protein that in humans is encoded by the KCNK3 gene.[1][2][3][4]
This gene encodes K2P3.1, one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. K2P3.1 is an outwardly rectifying channel that is sensitive to changes in extracellular pH and is inhibited by extracellular acidification. Also referred to as an acid-sensitive potassium channel, it is activated by the anesthetics halothane and isoflurane. Although three transcripts are detected in northern blots, there is currently no sequence available to confirm transcript variants for this gene.[4]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
# Interactions
KCNK3 has been shown to interact with YWHAB[5] and S100A10.[6] | https://www.wikidoc.org/index.php/KCNK3 | |
144ecf09145384ef007d54ecfcf63f4cda3e8ef0 | wikidoc | KCNK4 | KCNK4
Potassium channel subfamily K member 4 is a protein that in humans is encoded by the KCNK4 gene.
# Function
Potassium channels play a role in many cellular processes including maintenance of the action potential, muscle contraction, hormone secretion, osmotic regulation, and ion flow. This gene encodes the K2P4.1 protein, one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. K2P4.1 homodimerizes and functions as an outwardly rectifying channel. It is expressed primarily in neural tissues and is stimulated by membrane stretch and polyunsaturated fatty acids.
KCNK4 protein channels are also called TRAAK channels. TRAAK channels are found in mammalian neurons and are part of a protein family of weakly inward rectifying potassium channels. This subfamily of potassium channels is mechanically gated. The C-terminal of TRAAK has a charged cluster that is important in maintaining the mechanosensitive properties of the channel.
TRAAK is only expressed in neuronal tissue, and can be found in the brain, spinal cord, and retina, which suggests that it has a function beyond mechanotransduction in terms of neuronal excitability. The highest levels of TRAAK expression are in the olfactory system, cerebral cortex, hippocampal formation, habenula, basal ganglia, and cerebellum. TRAAK channels are mechanically activated when there is a convex curvature in the membrane that alters the channel’s activity. TRAAK channels are thought to have a role in axonal pathfinding, growth cone motility, and neurite elongation, as well as possibly having a role in touch or pain detection. | KCNK4
Potassium channel subfamily K member 4 is a protein that in humans is encoded by the KCNK4 gene.[1][2][3]
# Function
Potassium channels play a role in many cellular processes including maintenance of the action potential, muscle contraction, hormone secretion, osmotic regulation, and ion flow. This gene encodes the K2P4.1 protein, one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. K2P4.1 homodimerizes and functions as an outwardly rectifying channel. It is expressed primarily in neural tissues and is stimulated by membrane stretch and polyunsaturated fatty acids.[3]
KCNK4 protein channels are also called TRAAK channels. TRAAK channels are found in mammalian neurons and are part of a protein family of weakly inward rectifying potassium channels. This subfamily of potassium channels is mechanically gated. The C-terminal of TRAAK has a charged cluster that is important in maintaining the mechanosensitive properties of the channel.[4]
TRAAK is only expressed in neuronal tissue, and can be found in the brain, spinal cord, and retina, which suggests that it has a function beyond mechanotransduction in terms of neuronal excitability.[5] The highest levels of TRAAK expression are in the olfactory system, cerebral cortex, hippocampal formation, habenula, basal ganglia, and cerebellum.[5] TRAAK channels are mechanically activated when there is a convex curvature in the membrane that alters the channel’s activity. TRAAK channels are thought to have a role in axonal pathfinding, growth cone motility, and neurite elongation, as well as possibly having a role in touch or pain detection.[6][7] | https://www.wikidoc.org/index.php/KCNK4 | |
80db6cde44d887909242657b5afb1eee7617fe89 | wikidoc | KCNK9 | KCNK9
Potassium channel subfamily K member 9 is a protein that in humans is encoded by the KCNK9 gene.
This gene encodes K2P9.1, one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. This open channel is highly expressed in the cerebellum. It is inhibited by extracellular acidification and arachidonic acid, and strongly inhibited by phorbol 12-myristate 13-acetate. Phorbol 12-myristate 13-acetate is also known as 12-O-tetradecanoylphorbol-13-acetate (TPA). TASK channels are additionally inhibited by hormones and transmitters that signal through GqPCRs. The resulting cellular depolarization is thought to regulate processes such as motor control and aldosterone secretion. Despite early controversy about the exact mechanism underlying this inhibition, the current view is that Diacyl-glycerol, produced by the breakdown of Phosphatidylinositol-4,5-bis-phosphate by Phospholipase Cβ causes channel closure.
# Expression
The KCNK9 gene is expressed as an ion channel more commonly known as TASK 3. This channel has a varied pattern of expression. TASK 3 is coexpressed with TASK 1 (KCNK3) in the cerebellar granule cells, locus coeruleus, motor neurons, pontine nuclei, some cells in the neocortex, habenula, olfactory bulb granule cells, and cells in the external plexiform layer of the olfactory bulb. TASK-3 channels are also expressed in the hippocampus; both on pyramidal cells and interneurons. It is thought that these channels may form heterodimers where their expressions co-localise.
# Function
Mice in which the TASK-3 gene has been deleted have reduced sensitivity to inhalation anaesthetics, exaggerated nocturnal activity and cognitive deficits as well as significantly increased appetite and weight gain. A role for TASK-3 channels in neuronal network oscillations has also been described: TASK-3 knockout mice lack the atropine-sensitive halothane-induced theta oscillation (4–7 Hz) from the hippocampus and are unable to maintain theta oscillations during rapid eye movement (REM) sleep.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | KCNK9
Potassium channel subfamily K member 9 is a protein that in humans is encoded by the KCNK9 gene.[1][2][3]
This gene encodes K2P9.1, one of the members of the superfamily of potassium channel proteins containing two pore-forming P domains. This open channel is highly expressed in the cerebellum. It is inhibited by extracellular acidification and arachidonic acid, and strongly inhibited by phorbol 12-myristate 13-acetate.[3] Phorbol 12-myristate 13-acetate is also known as 12-O-tetradecanoylphorbol-13-acetate (TPA). TASK channels are additionally inhibited by hormones and transmitters that signal through GqPCRs. The resulting cellular depolarization is thought to regulate processes such as motor control and aldosterone secretion. Despite early controversy about the exact mechanism underlying this inhibition, the current view is that Diacyl-glycerol, produced by the breakdown of Phosphatidylinositol-4,5-bis-phosphate by Phospholipase Cβ causes channel closure. [4]
# Expression
The KCNK9 gene is expressed as an ion channel more commonly known as TASK 3. This channel has a varied pattern of expression. TASK 3 is coexpressed with TASK 1 (KCNK3) in the cerebellar granule cells, locus coeruleus, motor neurons, pontine nuclei, some cells in the neocortex, habenula, olfactory bulb granule cells, and cells in the external plexiform layer of the olfactory bulb.[5] TASK-3 channels are also expressed in the hippocampus; both on pyramidal cells and interneurons.[6] It is thought that these channels may form heterodimers where their expressions co-localise.[7][8]
# Function
Mice in which the TASK-3 gene has been deleted have reduced sensitivity to inhalation anaesthetics, exaggerated nocturnal activity and cognitive deficits as well as significantly increased appetite and weight gain.[9][10] A role for TASK-3 channels in neuronal network oscillations has also been described: TASK-3 knockout mice lack the atropine-sensitive halothane-induced theta oscillation (4–7 Hz) from the hippocampus and are unable to maintain theta oscillations during rapid eye movement (REM) sleep.[10]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/KCNK9 | |
99994b3e41fb21d7095cd020ebe835a03abe4a0d | wikidoc | KCNN2 | KCNN2
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2, also known as KCNN2, is a protein which in humans is encoded by the KCNN2 gene. KCNN2 is an ion channel protein also known as KCa2.2.
# Function
Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. The KCa2.2 protein is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. KCa2.2 is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. This protein is a member of the calcium-activated potassium channel family. Two transcript variants encoding different isoforms have been found for the KCNN2 gene.
In a study SK2 (KCNN2) potassium channel was overexpressed in the basolateral amygdala using a herpes simplex viral system. This reduced anxiety and stress-induced corticosterone secretion at a systemic level. SK2 overexpression also reduced dendritic arborization of the amygdala neurons. | KCNN2
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2, also known as KCNN2, is a protein which in humans is encoded by the KCNN2 gene.[1] KCNN2 is an ion channel protein also known as KCa2.2.[2]
# Function
Action potentials in vertebrate neurons are followed by an afterhyperpolarization (AHP) that may persist for several seconds and may have profound consequences for the firing pattern of the neuron. Each component of the AHP is kinetically distinct and is mediated by different calcium-activated potassium channels. The KCa2.2 protein is activated before membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic AHP. KCa2.2 is an integral membrane protein that forms a voltage-independent calcium-activated channel with three other calmodulin-binding subunits. This protein is a member of the calcium-activated potassium channel family. Two transcript variants encoding different isoforms have been found for the KCNN2 gene.[2]
In a study SK2 (KCNN2) potassium channel was overexpressed in the basolateral amygdala using a herpes simplex viral system. This reduced anxiety and stress-induced corticosterone secretion at a systemic level. SK2 overexpression also reduced dendritic arborization of the amygdala neurons.[3] | https://www.wikidoc.org/index.php/KCNN2 | |
c18b505657fbe3e448b63ed52d64a547612507a2 | wikidoc | KCNN4 | KCNN4
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4, also known as KCNN4, is a human gene encoding the KCa3.1 protein.
# Function
The KCa3.1 protein is part of a potentially heterotetrameric voltage-independent potassium channel that is activated by intracellular calcium. Activation is followed by membrane hyperpolarization, which promotes calcium influx. The encoded protein may be part of the predominant calcium-activated potassium channel in T-lymphocytes. This gene is similar to other KCNN family potassium channel genes, but it differs enough to possibly be considered as part of a new subfamily.
# History
The channel activity was first described in 1958 by György Gárdos in human erythrocytes. The channels is also named Gardos channel because of its discoverer. | KCNN4
Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4, also known as KCNN4, is a human gene encoding the KCa3.1 protein.[1]
# Function
The KCa3.1 protein is part of a potentially heterotetrameric voltage-independent potassium channel that is activated by intracellular calcium. Activation is followed by membrane hyperpolarization, which promotes calcium influx. The encoded protein may be part of the predominant calcium-activated potassium channel in T-lymphocytes. This gene is similar to other KCNN family potassium channel genes, but it differs enough to possibly be considered as part of a new subfamily.[1]
# History
The channel activity was first described in 1958 by György Gárdos in human erythrocytes.[2] The channels is also named Gardos channel because of its discoverer. | https://www.wikidoc.org/index.php/KCNN4 | |
15c472951f0e8f5d06936b11a9f1b1073454468e | wikidoc | KCNQ4 | KCNQ4
Potassium voltage-gated channel subfamily KQT member 4 also known as voltage-gated potassium channel subunit Kv7.4 is a protein that in humans is encoded by the KCNQ4 gene.
# Function
The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene.
# Clinical significance
The current generated by this channel is inhibited by muscarinic acetylcholine receptor M1 and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene.
# Ligands
- ML213: KCNQ2/Q4 channel opener. | KCNQ4
Potassium voltage-gated channel subfamily KQT member 4 also known as voltage-gated potassium channel subunit Kv7.4 is a protein that in humans is encoded by the KCNQ4 gene.[1][2][3]
# Function
The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene.[3]
# Clinical significance
The current generated by this channel is inhibited by muscarinic acetylcholine receptor M1 and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene.[3]
# Ligands
- ML213: KCNQ2/Q4 channel opener.[4] | https://www.wikidoc.org/index.php/KCNQ4 | |
066cd9c08d9b49ab977871d8e07bbbb26fdcb97e | wikidoc | KCNRG | KCNRG
Potassium channel regulator, also known as KCNRG, is a protein which in humans is encoded by theKCNRG gene.
# Function
KCNRG is a soluble protein with characteristics suggesting it forms hetero-tetramers with voltage-gated K+ channels and inhibits their function.
# Clinical significance
KCNRG has been found to be predominantly expressed in lung tissue. Additionally, KCNRG transcripts are also found in liver and some other tissues, but in lower extent.
Researchers at Uppsala University have found that KCNRG is found in the lower lung and constitutes an autoantigen in a rare disorder named autoimmune polyendocrine syndrome type 1 (APS1). As a subset of patients with APS1 suffer from respiratory disease, an autoimmune reaction against KCNRG may explain the respiratory disease in these patients. KCNRG may also be connected to common nonfatal diseases like asthma and chronic bronchitis. | KCNRG
Potassium channel regulator, also known as KCNRG, is a protein which in humans is encoded by theKCNRG gene.[1][2]
# Function
KCNRG is a soluble protein with characteristics suggesting it forms hetero-tetramers with voltage-gated K+ channels and inhibits their function.[1]
# Clinical significance
KCNRG has been found to be predominantly expressed in lung tissue. Additionally, KCNRG transcripts are also found in liver and some other tissues, but in lower extent.
Researchers at Uppsala University have found that KCNRG is found in the lower lung and constitutes an autoantigen in a rare disorder named autoimmune polyendocrine syndrome type 1 (APS1). As a subset of patients with APS1 suffer from respiratory disease, an autoimmune reaction against KCNRG may explain the respiratory disease in these patients. KCNRG may also be connected to common nonfatal diseases like asthma and chronic bronchitis.[3] | https://www.wikidoc.org/index.php/KCNRG | |
e296d2dfd02025f2b7057b54da316c290cc3c26a | wikidoc | KCTD7 | KCTD7
Potassium channel tetramerisation domain containing 7 is a protein in humans that is encoded by the KCTD7 gene. Alternative splicing results in multiple transcript variants.
# Description
The KCTD7 gene encodes a member of the potassium channel tetramerisation domain-containing protein family. Family members are identified on a structural basis and contain an amino-terminal domain similar to the T1 domain present in the voltage-gated potassium channel. KCTD7 displays a primary sequence and hydropathy profile indicating intracytoplasmic localization. EST database analysis showed that KCTD7 is expressed in human and mouse brain.
# Function
KCTD7 expression hyperpolarizes the cell membrane and reduces the excitability of transfected neurons in patch clamp experiments. KCTD7 mRNA and protein are expressed in hippocampal neurons, deep layers of the cerebral cortex and Purkinje cells of the murine brain as shown by in situ hybridization and immunohistochemistry experiments. Immunoprecipitation assays demonstrates that KCTD7 is able to prudhommerie and directly interacts with cullin-3 (CUL3), a component of the ubiquitin ligase complex. These interactions are thought to be mediated via the BTB/POZ domain of KCTD7. However, KCTD7 does not show any interaction cullin-1 (CUL1). Immunoprecipitation assays also shows that KCTD7 does not interact with Ubiquitin-flag, suggesting a potential role of KCTD7 in the ubiquitin ligase complex without being itself subject to uiquitination. Immunofluorescence microscopy shows a cytosolic expression of the recombinant GFP-KCTD7 protein in transfected COS-7 cells.
One possible hypothesis is that KCTD7 regulates indirectly the membrane expression level of a potassium channel. By conjugating with cullin-3 ubiquitin ligase complex, KCTD7 may modulate the expression level of a negative regulator of potassium channel. Therefore, the overexpression of KCTD7 in neurons would increase the degradation of that regulatory molecule leading to the increase of potassium current through the cell membrane as observed in patch clamp experiments.
In cultured mouse hippocampal cells, expression is found in the cell soma, in neuritic varicosities along the developing neuronal extensions, and in neurite growth cones, but not in the nucleus. Kctd7 is widely expressed in neurons throughout the intact mouse brain, including in cortical neurons, in granular and pyramidal cell layers of the hippocampus, and in cerebellar Purkinje cells. However, not all neuronal cells are immunopositive for Kctd7, and expression is not seen in astrocytes or microglial cells. Expression is constant from P5 to 2 months in cerebellar lysates. Overexpression of KCTD7 in HeLa and COS-1 cells, which do not express endogenous KCTD7, shows diffuse cytosolic localization, with no colocalization with markers for endosomes, ER, Golgi, lysosomes, or the cytoskeleton.
Beside the BTB/POZ domain of KCTD7, other residues are critical for its proper interaction with cullin-3. Furthermore, a full-length 31-kD Kctd7 isoform is expressed in mouse brain. Other major immunoreactive bands included a 28-kD species in the spleen, liver, and kidneys, a 37-kD species in the kidneys, and a 62-kD form most likely corresponding to a stable dimer. The presence of multiple bands was consistent with alternative splicing and tissue-specific regulation.
# Clinical significance
In 3 affected members of a large consanguineous Moroccan family with progressive myoclonic epilepsy-3, a homozygous nonsense mutation in the KCTD7 gene (R99X) has been identified.
In 2 Mexican siblings with infantile onset of progressive myoclonic epilepsy and pathologic findings of neuronal ceroid lipofuscinosis in multiple cell types, a homozygous mutation in the KCTD7 gene (R184C) has been identified. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. This phenotype has been identified as CLN14. KCTD7 mutations were not found in 32 additional CLN samples. | KCTD7
Potassium channel tetramerisation domain containing 7 is a protein in humans that is encoded by the KCTD7 gene.[1] Alternative splicing results in multiple transcript variants.
# Description
The KCTD7 gene encodes a member of the potassium channel tetramerisation domain-containing protein family. Family members are identified on a structural basis and contain an amino-terminal domain similar to the T1 domain present in the voltage-gated potassium channel.[1] KCTD7 displays a primary sequence and hydropathy profile indicating intracytoplasmic localization. EST database analysis showed that KCTD7 is expressed in human and mouse brain.[2]
# Function
KCTD7 expression hyperpolarizes the cell membrane and reduces the excitability of transfected neurons in patch clamp experiments.[3] KCTD7 mRNA and protein are expressed in hippocampal neurons, deep layers of the cerebral cortex and Purkinje cells of the murine brain as shown by in situ hybridization and immunohistochemistry experiments. Immunoprecipitation assays demonstrates that KCTD7 is able to prudhommerie and directly interacts with cullin-3 (CUL3), a component of the ubiquitin ligase complex. These interactions are thought to be mediated via the BTB/POZ domain of KCTD7. However, KCTD7 does not show any interaction cullin-1 (CUL1). Immunoprecipitation assays also shows that KCTD7 does not interact with Ubiquitin-flag, suggesting a potential role of KCTD7 in the ubiquitin ligase complex without being itself subject to uiquitination. Immunofluorescence microscopy shows a cytosolic expression of the recombinant GFP-KCTD7 protein in transfected COS-7 cells.
One possible hypothesis is that KCTD7 regulates indirectly the membrane expression level of a potassium channel. By conjugating with cullin-3 ubiquitin ligase complex, KCTD7 may modulate the expression level of a negative regulator of potassium channel. Therefore, the overexpression of KCTD7 in neurons would increase the degradation of that regulatory molecule leading to the increase of potassium current through the cell membrane as observed in patch clamp experiments.
In cultured mouse hippocampal cells, expression is found in the cell soma, in neuritic varicosities along the developing neuronal extensions, and in neurite growth cones, but not in the nucleus.[4] Kctd7 is widely expressed in neurons throughout the intact mouse brain, including in cortical neurons, in granular and pyramidal cell layers of the hippocampus, and in cerebellar Purkinje cells. However, not all neuronal cells are immunopositive for Kctd7, and expression is not seen in astrocytes or microglial cells. Expression is constant from P5 to 2 months in cerebellar lysates. Overexpression of KCTD7 in HeLa and COS-1 cells, which do not express endogenous KCTD7, shows diffuse cytosolic localization, with no colocalization with markers for endosomes, ER, Golgi, lysosomes, or the cytoskeleton.
Beside the BTB/POZ domain of KCTD7, other residues are critical for its proper interaction with cullin-3.[5] Furthermore, a full-length 31-kD Kctd7 isoform is expressed in mouse brain. Other major immunoreactive bands included a 28-kD species in the spleen, liver, and kidneys, a 37-kD species in the kidneys, and a 62-kD form most likely corresponding to a stable dimer. The presence of multiple bands was consistent with alternative splicing and tissue-specific regulation.
# Clinical significance
In 3 affected members of a large consanguineous Moroccan family with progressive myoclonic epilepsy-3, a homozygous nonsense mutation in the KCTD7 gene (R99X) has been identified.[2]
In 2 Mexican siblings with infantile onset of progressive myoclonic epilepsy and pathologic findings of neuronal ceroid lipofuscinosis in multiple cell types, a homozygous mutation in the KCTD7 gene (R184C) has been identified.[5] The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. This phenotype has been identified as CLN14. KCTD7 mutations were not found in 32 additional CLN samples.[5] | https://www.wikidoc.org/index.php/KCTD7 | |
88848c2b8fe4f7cd4c5a6b164fb43f8fe2c12f10 | wikidoc | KDM1A | KDM1A
Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein in humans that is encoded by the KDM1A gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysines 4 and 9 (H3K4 and H3K9). This enzyme can have roles critical in embryogenesis and tissue-specific differentiation, as well as oocyte growth. KDM1A was the first histone demethylase to be discovered though more than 30 have been described.
# Structure
This gene encodes a nuclear protein containing a SWIRM domain, a FAD-binding motif, and an amine oxidase domain. This protein is a component of several histone deacetylase complexes, though it silences genes by functioning as a histone demethylase.
# Function
LSD1 (lysine-specific demethylase 1), also known as KDM1, is the first of several protein lysine demethylases discovered. Through a FAD-dependent oxidative reaction, LSD1 specifically removes histone H3K4me2 to H3K4me1 or H3K4me0. When forming a complex with androgen receptor (and possibly other nuclear hormone receptors), LSD1 changes its substrates to H3K9me2. It's now known LSD1 complex mediates a coordinated histone modification switch through enzymatic activities as well as histone modification readers in the complex.
Function of KDM1A gene can be effectively examined by siRNA knockdown based on an independent validation.
# Interactions
KDM1A has many different binding partners, which may be necessary for its demethylation activity.
# Clinical significance
KDM1A appears to play an important role in the epigenetic "reprogramming" that occurs when sperm and egg come together to make a zygote. Deletion of the gene for KDM1A can have effects on the growth and differentiation of embryonic stem cells. Deletion in mouse embryos is lethal; embryos do not progress beyond Day 7.5. KDM1A is also thought to play a role in cancer, as poorer outcomes can be correlated with higher expression of this gene. Therefore, the inhibition of KDM1A may be a possible treatment for cancer.
# Mutations
De novo mutations to KDM1A have been reported in three patients, each with developmental delays believed to be attributable in part to the mutations. All documented mutations are missense substitutions. One of the affected families has created a public website in order to identify further cases. | KDM1A
Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein in humans that is encoded by the KDM1A gene.[1] LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and di-methylated lysines, specifically histone 3, lysines 4 and 9 (H3K4 and H3K9).[2] This enzyme can have roles critical in embryogenesis and tissue-specific differentiation, as well as oocyte growth.[3] KDM1A was the first histone demethylase to be discovered though more than 30 have been described.[4]
# Structure
This gene encodes a nuclear protein containing a SWIRM domain, a FAD-binding motif, and an amine oxidase domain. This protein is a component of several histone deacetylase complexes, though it silences genes by functioning as a histone demethylase.
# Function
LSD1 (lysine-specific demethylase 1), also known as KDM1, is the first of several protein lysine demethylases discovered. Through a FAD-dependent oxidative reaction, LSD1 specifically removes histone H3K4me2 to H3K4me1 or H3K4me0. When forming a complex with androgen receptor (and possibly other nuclear hormone receptors), LSD1 changes its substrates to H3K9me2. It's now known LSD1 complex mediates a coordinated histone modification switch through enzymatic activities as well as histone modification readers in the complex.
Function of KDM1A gene can be effectively examined by siRNA knockdown based on an independent validation.[5]
# Interactions
KDM1A has many different binding partners, which may be necessary for its demethylation activity.[6]
# Clinical significance
KDM1A appears to play an important role in the epigenetic "reprogramming" that occurs when sperm and egg come together to make a zygote.[7][8] Deletion of the gene for KDM1A can have effects on the growth and differentiation of embryonic stem cells.[9] Deletion in mouse embryos is lethal; embryos do not progress beyond Day 7.5.[10][11] KDM1A is also thought to play a role in cancer, as poorer outcomes can be correlated with higher expression of this gene.[12][13] Therefore, the inhibition of KDM1A may be a possible treatment for cancer.[14][15][16][17]
# Mutations
De novo mutations to KDM1A have been reported in three patients, each with developmental delays believed to be attributable in part to the mutations.[18][19] All documented mutations are missense substitutions.[20][21][22] One of the affected families has created a public website in order to identify further cases.[23] | https://www.wikidoc.org/index.php/KDM1A | |
7818237412722bafe1e7bc734cb9b39e37b1b8a4 | wikidoc | KDM2A | KDM2A
Lysine-specific demethylase 2A (KDM2A) also known as F-box and leucine-rich repeat protein 11 (FBXL11) is an enzyme that in humans is encoded by the KDM2A gene. KDM2A is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylases, which are non-haem iron-containing proteins.
# Function
This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains at least 6 highly degenerated leucine-rich repeats.
FBXL11/KDM2A is a histone H3 lysine 36 demethylase enzyme. The enzymatic activity of FBXL11/KDM2A relies on a conserved JmjC domain in the N-terminus of the protein that co-ordinates iron and alphaketoglutarate to catalyze demethylation via a hydroxylation based mechanism. It has recently been demonstrated that a ZF-CxxC DNA binding domain within FBXL11/KDM2A has the capacity to interact with non-methylated DNA and this domain targets FBXL11/KDM2A to CpG island regions of the genome where it specifically removes histone H3 lysine 36 methylation. This mechanism acts to create a chromatin environment at CpG islands that highlights these regulatory elements and differentiates them from non-regulatory regions in large complex mammalian genomes. In a study in mouse hepatocytes, this gene was shown to regulate hepatic gluconeogenesis. | KDM2A
Lysine-specific demethylase 2A (KDM2A) also known as F-box and leucine-rich repeat protein 11 (FBXL11) is an enzyme that in humans is encoded by the KDM2A gene.[1][2][3] KDM2A is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylases, which are non-haem iron-containing proteins.
# Function
This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains at least 6 highly degenerated leucine-rich repeats.[3]
FBXL11/KDM2A is a histone H3 lysine 36 demethylase enzyme. The enzymatic activity of FBXL11/KDM2A relies on a conserved JmjC domain in the N-terminus of the protein that co-ordinates iron and alphaketoglutarate to catalyze demethylation via a hydroxylation based mechanism.[4] It has recently been demonstrated that a ZF-CxxC DNA binding domain within FBXL11/KDM2A has the capacity to interact with non-methylated DNA and this domain targets FBXL11/KDM2A to CpG island regions of the genome where it specifically removes histone H3 lysine 36 methylation.[5] This mechanism acts to create a chromatin environment at CpG islands that highlights these regulatory elements and differentiates them from non-regulatory regions in large complex mammalian genomes. In a study in mouse hepatocytes, this gene was shown to regulate hepatic gluconeogenesis.[6] | https://www.wikidoc.org/index.php/KDM2A | |
bf2f54642f983bf34b758b876065062f07bc87fb | wikidoc | KDM2B | KDM2B
The human KDM2B gene encodes the protein Lysine (K)-specific demethylase 2B.
# Tissue and subcellular distribution
KDM2B is broadly and highly expressed in embryonic tissues (especially in the developing central nervous system of vertebrates). Expression of KDM2B is also retained in most organs in adults. The protein is present in the nucleoplasm and is enriched in the nucleolus where it binds the transcribed region of ribosomal RNA to represses the transcription of ribosomal RNA genes which inhibits cell growth and proliferation.
# Structure
KDM2B protein has several domains including a JmjC domain that has a histone demethylase activity demethylating trimethylated Lys-4 and dimethylated Lys-36 of histone H3. It is also the core scaffold of the non-canonical polycomb repressive complex 1.1 (ncPRC1.1) containing BCOR, PCGF1, RING1/2 and RYBP that mono-ubiquitylates histone H2A on K119.
# Function
This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been determined.
As part of the ncPRC1.1 complex, KDM2B was found to rapidly and transiently recruite to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of histone H2A on K119 with concomitant local decrease of H2A levels and an increase of H2A.Z. These events promote transcriptional repression at DNA lesions, double strand break signaling, and homologous recombination repair. The activity of the ncPRC1.1 complex at DNA lesions was necessary for the proper recruitment of the two canonical PRC1 complexes (cPRC1.2 and cPRC1.4), defined by their PCGF subunits, MEL18 and BMI1 respectively. Therefore, recruitment of the ncPRC1.1 complex represents an early and critical regulatory step in homologous recombination repair.
# Clinical significance
Loss of KDM2B leads to severe developmental defects (growth defects in the brain, including failure of neural tube closure and craniofacial malformations, hematopoietic development) leading to embryonic lethality | KDM2B
The human KDM2B gene encodes the protein Lysine (K)-specific demethylase 2B.[1]
# Tissue and subcellular distribution
KDM2B is broadly and highly expressed in embryonic tissues (especially in the developing central nervous system of vertebrates). Expression of KDM2B is also retained in most organs in adults.[2] The protein is present in the nucleoplasm and is enriched in the nucleolus where it binds the transcribed region of ribosomal RNA to represses the transcription of ribosomal RNA genes which inhibits cell growth and proliferation.[3]
# Structure
KDM2B protein has several domains including a JmjC domain that has a histone demethylase activity demethylating trimethylated Lys-4 and dimethylated Lys-36 of histone H3.[4][3] It is also the core scaffold of the non-canonical polycomb repressive complex 1.1 (ncPRC1.1) containing BCOR, PCGF1, RING1/2 and RYBP that mono-ubiquitylates histone H2A on K119.[5][6][7][8]
# Function
This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been determined.[1]
As part of the ncPRC1.1 complex, KDM2B was found to rapidly and transiently recruite to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of histone H2A on K119 with concomitant local decrease of H2A levels and an increase of H2A.Z. These events promote transcriptional repression at DNA lesions, double strand break signaling, and homologous recombination repair. The activity of the ncPRC1.1 complex at DNA lesions was necessary for the proper recruitment of the two canonical PRC1 complexes (cPRC1.2 and cPRC1.4), defined by their PCGF subunits, MEL18 and BMI1 respectively. Therefore, recruitment of the ncPRC1.1 complex represents an early and critical regulatory step in homologous recombination repair.[9]
# Clinical significance
Loss of KDM2B leads to severe developmental defects (growth defects in the brain, including failure of neural tube closure and craniofacial malformations, hematopoietic development) leading to embryonic lethality[10] | https://www.wikidoc.org/index.php/KDM2B | |
1baaa4dd90781d7c1660977bb21ee814360f986c | wikidoc | KDM4A | KDM4A
Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the KDM4A gene.
# Function
This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein with a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily. It functions as a trimethylation-specific demethylase, converting specific trimethylated histone on histone H3 lysine 9 and 36 residues to the dimethylated form and lysine 9 dimethylated residues to monomethyl, and as a transcriptional repressor.
Alterations in this gene have been found associated with chromosomal instability that leads to cancer.(.mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}PMID 23871696) | KDM4A
Lysine-specific demethylase 4A is an enzyme that in humans is encoded by the KDM4A gene.[1][2][3]
# Function
This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein with a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily. It functions as a trimethylation-specific demethylase, converting specific trimethylated histone on histone H3 lysine 9 and 36 residues to the dimethylated form and lysine 9 dimethylated residues to monomethyl, and as a transcriptional repressor.[3]
Alterations in this gene have been found associated with chromosomal instability that leads to cancer.(.mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}PMID 23871696) | https://www.wikidoc.org/index.php/KDM4A | |
b6418ab12d7ab616e24c7a6c8f8cf10779bbd1ec | wikidoc | KDM4C | KDM4C
Lysine-specific demethylase 4C is an enzyme that in humans is encoded by the KDM4C gene.
# Function
This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein with one JmjC domain, one JmjN domain, two PHD-type zinc fingers, and two Tudor domains. This nuclear protein belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily. It functions as a trimethylation-specific demethylase, converting specific trimethylated histone residues to the dimethylated form. Chromosomal aberrations and increased transcriptional expression of this gene are associated with esophageal squamous cell carcinoma. A expressional decrease of KDM4C was found during cardiac differentation of murine embryonic stem cells.
# Model organisms
Model organisms have been used in the study of KDM4C function. A conditional knockout mouse line, called Kdm4ctm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant males had decreased haematocrit and haemoglobin levels, while animals of both sex displayed an increase in sebaceous gland size. | KDM4C
Lysine-specific demethylase 4C is an enzyme that in humans is encoded by the KDM4C gene.[1][2][3]
# Function
This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein with one JmjC domain, one JmjN domain, two PHD-type zinc fingers, and two Tudor domains. This nuclear protein belongs to the alpha-ketoglutarate-dependent hydroxylase superfamily. It functions as a trimethylation-specific demethylase, converting specific trimethylated histone residues to the dimethylated form. Chromosomal aberrations and increased transcriptional expression of this gene are associated with esophageal squamous cell carcinoma.[3] A expressional decrease of KDM4C was found during cardiac differentation of murine embryonic stem cells.[4]
# Model organisms
Model organisms have been used in the study of KDM4C function. A conditional knockout mouse line, called Kdm4ctm1a(KOMP)Wtsi[10][11] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[12][13][14]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[8] Homozygous mutant males had decreased haematocrit and haemoglobin levels, while animals of both sex displayed an increase in sebaceous gland size.[8] | https://www.wikidoc.org/index.php/KDM4C | |
54f0df1a0d6ec022db214ffd6fa788650d4458d9 | wikidoc | KDM5A | KDM5A
Lysine-specific demethylase 5A is an enzyme that in humans is encoded by the KDM5A gene.
# Function
The protein encoded by this gene is a ubiquitously expressed nuclear protein. It binds directly, with several other proteins, to retinoblastoma protein which regulates cell proliferation. It was formerly known as Retinoblastoma Binding Protein 2 (RBP2). This protein also interacts with rhombotin-2 which functions distinctly in erythropoiesis and in T-cell leukemogenesis. Rhombotin-2 is thought to either directly affect the activity of the encoded protein or may indirectly modulate the functions of the retinoblastoma protein by binding to this protein. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
The Drosophila homolog, LID, was found to be an H3K4 histone demethylase that binds to c-Myc. It was recently renamed to Lysine Demethylase 5A (KDM5A).
Enzymatically can be designated as a trimethyllysine dioxygenase, which is a member of the alpha-ketoglutarate-dependent hydroxylase superfamily (EC 1.14.11.8).
# Interactions
JARID1A has been shown to interact with Estrogen receptor alpha, LMO2 and Retinoblastoma protein.
JARID1A is a major component of the circadian clock, the upregulation of which at the end of the sleep phase blocks HDAC1 activity. Blocking HDAC1 activity results in an upregulation of CLOCK and BMAL1 and consequent upregulation of PER proteins. The PSF (polypyrimidine tract-binding protein-associated splicing factor) within the PER complex recruits SIN3A, a scaffold for assembly of transcriptional inhibitory complexes and rhythmically delivers histone deacetylases to the Per1 promoter, which repress Per1 transcription.
Knockdown of JARID1A promoted osteogenic differentiation of human adipose-derived stromal cells in vitro and in vivo and resulted in marked increases of mRNA expression of osteogenesis-associated genes such as alkaline phosphatase (ALP), osteocalcin (OC), and osterix (OSX). RBP2 was shown to occupy the promoters of OSX and OC to maintain the level of the H3K4me3 mark by chromatin immunoprecipitation assays. RBP2 was also physically and functionally associated with RUNX2, an essential transcription factor that governed osteoblastic differentiation. RUNX2 knockdown impaired the repressive activity of RBP2 in osteogenic differentiation of human adipose-derived stromal cells. | KDM5A
Lysine-specific demethylase 5A is an enzyme that in humans is encoded by the KDM5A gene.[1][2]
# Function
The protein encoded by this gene is a ubiquitously expressed nuclear protein. It binds directly, with several other proteins, to retinoblastoma protein which regulates cell proliferation. It was formerly known as Retinoblastoma Binding Protein 2 (RBP2). This protein also interacts with rhombotin-2 which functions distinctly in erythropoiesis and in T-cell leukemogenesis. Rhombotin-2 is thought to either directly affect the activity of the encoded protein or may indirectly modulate the functions of the retinoblastoma protein by binding to this protein. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[2]
The Drosophila homolog, LID, was found to be an H3K4 histone demethylase that binds to c-Myc.[3] It was recently renamed to Lysine Demethylase 5A (KDM5A).
Enzymatically can be designated as a trimethyllysine dioxygenase, which is a member of the alpha-ketoglutarate-dependent hydroxylase superfamily (EC 1.14.11.8).
# Interactions
JARID1A has been shown to interact with Estrogen receptor alpha,[4] LMO2[5] and Retinoblastoma protein.[4][6]
JARID1A is a major component of the circadian clock, the upregulation of which at the end of the sleep phase blocks HDAC1 activity. Blocking HDAC1 activity results in an upregulation of CLOCK and BMAL1 and consequent upregulation of PER proteins. The PSF (polypyrimidine tract-binding protein-associated splicing factor) within the PER complex recruits SIN3A, a scaffold for assembly of transcriptional inhibitory complexes and rhythmically delivers histone deacetylases to the Per1 promoter, which repress Per1 transcription.[7][8]
Knockdown of JARID1A promoted osteogenic differentiation of human adipose-derived stromal cells in vitro and in vivo and resulted in marked increases of mRNA expression of osteogenesis-associated genes such as alkaline phosphatase (ALP), osteocalcin (OC), and osterix (OSX). RBP2 was shown to occupy the promoters of OSX and OC to maintain the level of the H3K4me3 mark by chromatin immunoprecipitation assays. RBP2 was also physically and functionally associated with RUNX2, an essential transcription factor that governed osteoblastic differentiation. RUNX2 knockdown impaired the repressive activity of RBP2 in osteogenic differentiation of human adipose-derived stromal cells.[9] | https://www.wikidoc.org/index.php/KDM5A | |
f7ffb777d5a77c963a7edabb10dc5273720f8e97 | wikidoc | KDM6B | KDM6B
Lysine demethylase 6B is a protein that in humans is encoded by the KDM6B gene.
# Regulation during differentation
KDM6B was found to be expressional increased during cardiac and endothelial differentation of murine embryonic stem cells.
# Small molecule inhibition
A small molecule inhibition (GSK-J1) has been developed to inhibit jumonji domain of KDM6 histone demethylase family to modulate proinflammatory response in macrophage. | KDM6B
Lysine demethylase 6B is a protein that in humans is encoded by the KDM6B gene.
[1]
# Regulation during differentation
KDM6B was found to be expressional increased during cardiac and endothelial differentation of murine embryonic stem cells.[2]
# Small molecule inhibition
A small molecule inhibition (GSK-J1) has been developed to inhibit jumonji domain of KDM6 histone demethylase family to modulate proinflammatory response in macrophage.[3] | https://www.wikidoc.org/index.php/KDM6B | |
d145dadb3c46155726134fab02f8474b73d321a2 | wikidoc | KEAP1 | KEAP1
Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the Keap1 gene.
# Structure
Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 residue, which is one of the important cysteines in stress sensing. The intervening region (IVR) domain contains two critical cysteine residues, Cys273 and Cys288, which are a second group of cysteines important for stress sensing. A double glycine repeat (DGR) and C-terminal region (CTR) domains collaborate to form a β-propeller structure, which is where Keap1 interacts with Nrf2.
# Interactions
Keap1 has been shown to interact with Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of oxidative stress.
Under quiescent conditions, Nrf2 is anchored in the cytoplasm through binding to Keap1, which, in turn, facilitates the ubiquitination and subsequent proteolysis of Nrf2. Such sequestration and further degradation of Nrf2 in the cytoplasm are mechanisms for the repressive effects of Keap1 on Nrf2.
# As a drug target
Because Nrf2 activation leads to a coordinated antioxidant and anti-inflammatory response, and Keap1 represses Nrf2 activation, Keap1 has become a very attractive drug target.
A series of synthetic oleane triterpenoid compounds, known as antioxidant inflammation modulators (AIMs), are being developed by Reata Pharmaceuticals, Inc. and are potent inducers of the Keap1-Nrf2 pathway, blocking Keap1-dependent Nrf2 ubiquitination and leading to the stabilization and nuclear translocation of Nrf2 and subsequent induction of Nrf2 target genes. The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), was in late-stage clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus and showed an ability to improve markers of renal function in these patients. However, the Phase 3 trial was halted due to safety concerns. | KEAP1
Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the Keap1 gene.[1]
# Structure
Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 residue, which is one of the important cysteines in stress sensing. The intervening region (IVR) domain contains two critical cysteine residues, Cys273 and Cys288, which are a second group of cysteines important for stress sensing. A double glycine repeat (DGR) and C-terminal region (CTR) domains collaborate to form a β-propeller structure, which is where Keap1 interacts with Nrf2.
# Interactions
Keap1 has been shown to interact with Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of oxidative stress.[2][3][4]
Under quiescent conditions, Nrf2 is anchored in the cytoplasm through binding to Keap1, which, in turn, facilitates the ubiquitination and subsequent proteolysis of Nrf2. Such sequestration and further degradation of Nrf2 in the cytoplasm are mechanisms for the repressive effects of Keap1 on Nrf2.
# As a drug target
Because Nrf2 activation leads to a coordinated antioxidant and anti-inflammatory response, and Keap1 represses Nrf2 activation, Keap1 has become a very attractive drug target.[5][6][7][8]
A series of synthetic oleane triterpenoid compounds, known as antioxidant inflammation modulators (AIMs), are being developed by Reata Pharmaceuticals, Inc. and are potent inducers of the Keap1-Nrf2 pathway, blocking Keap1-dependent Nrf2 ubiquitination and leading to the stabilization and nuclear translocation of Nrf2 and subsequent induction of Nrf2 target genes.[citation needed] The lead compound in this series, bardoxolone methyl (also known as CDDO-Me or RTA 402), was in late-stage clinical trials for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes mellitus and showed an ability to improve markers of renal function in these patients.[citation needed] However, the Phase 3 trial was halted due to safety concerns. | https://www.wikidoc.org/index.php/KEAP1 | |
631eb29f9445e260202d5f7dbc9f8dfa32b25776 | wikidoc | KIF15 | KIF15
Kinesin family member 15 is a protein that in humans is encoded by the KIF15 gene.
This gene encodes a motor protein that is part of the kinesin superfamily. KIF15 maintains half spindle separation by opposing forces generated by other motor proteins. KIF15 co-localizes with microtubules and actin filaments in both dividing cells and in postmitotic neurons.
# Function
KIF15 (also known as Kinesin-12 and HKLP2) is a motor protein expressed in all cells during mitosis and in postmitotic neurons undergoing axon growth. KIF15 maintains bipolar microtubule spindle apparatus in dividing cells and shares redundant functions with KIF11. KIF15 is thought to promote spindle assembly by cross-linking and sliding along microtubules creating a separation between centrosomes. HeLa cells depleted of KIF11, with reduced microtubule dynamics, are able to form bipolar spindles from acentrosomal asters in a KIF15 dependent manner. Hence, inhibition of KIF15 function will be a vital therapeutic approach in cancer chemotherapy.
# Function in neurons
KIF15 restricts the movement of short microtubules into growing axons by generating forces on microtubules which counteract those generated by cytoplasmic dynein. KIF15, together with KIF23 become enriched in dendrites as neurons mature to promote the transport of minus-end distal microtubules into nascent dendrites.
# Interactions
KIF15 has been shown to interact with TPX2. Both these dimers cooperate to slide along microtubules and maintain bipolar spindles. | KIF15
Kinesin family member 15 is a protein that in humans is encoded by the KIF15 gene.[1]
This gene encodes a motor protein that is part of the kinesin superfamily. KIF15 maintains half spindle separation by opposing forces generated by other motor proteins. KIF15 co-localizes with microtubules and actin filaments in both dividing cells and in postmitotic neurons.[1]
# Function
KIF15 (also known as Kinesin-12 and HKLP2) is a motor protein expressed in all cells during mitosis and in postmitotic neurons undergoing axon growth.[2] KIF15 maintains bipolar microtubule spindle apparatus in dividing cells and shares redundant functions with KIF11.[3] KIF15 is thought to promote spindle assembly by cross-linking and sliding along microtubules creating a separation between centrosomes. HeLa cells depleted of KIF11, with reduced microtubule dynamics, are able to form bipolar spindles from acentrosomal asters in a KIF15 dependent manner.[4][5] Hence, inhibition of KIF15 function will be a vital therapeutic approach in cancer chemotherapy[6].
# Function in neurons
KIF15 restricts the movement of short microtubules into growing axons by generating forces on microtubules which counteract those generated by cytoplasmic dynein.[7][8] KIF15, together with KIF23 become enriched in dendrites as neurons mature to promote the transport of minus-end distal microtubules into nascent dendrites.[7]
# Interactions
KIF15 has been shown to interact with TPX2. Both these dimers cooperate to slide along microtubules and maintain bipolar spindles.[9][10] | https://www.wikidoc.org/index.php/KIF15 | |
950fef32286a50315abb12de02d170c346b7011b | wikidoc | KIF1A | KIF1A
Kinesin-like protein KIF1A, also known as axonal transporter of synaptic vesicles or microtubule-based motor KIF1A, is a protein that in humans is encoded by the KIF1A gene.
# Function
KIF1A is a member of the kinesin family. This protein is highly similar to mouse heavy-chain kinesin member 1A protein, which is an anterograde motor protein that transports membranous organelles along axonal microtubules. It is thought that this protein may play a critical role in the development of axonal neuropathies resulting from impaired axonal transport. There are multiple polyadenylation sites found in this gene. Sexual orientation has been linked to the regulatory domain of the gene.
# Clinical significance
KIF1A is associated with hereditary spastic paraparesis.
The website KIF1A.org serves as a resource for patients and care-givers, and provides links to research efforts. | KIF1A
Kinesin-like protein KIF1A, also known as axonal transporter of synaptic vesicles or microtubule-based motor KIF1A, is a protein that in humans is encoded by the KIF1A gene.[1][2][3]
# Function
KIF1A is a member of the kinesin family. This protein is highly similar to mouse heavy-chain kinesin member 1A protein, which is an anterograde motor protein that transports membranous organelles along axonal microtubules. It is thought that this protein may play a critical role in the development of axonal neuropathies resulting from impaired axonal transport. There are multiple polyadenylation sites found in this gene.[1] Sexual orientation has been linked to the regulatory domain of the gene.[4]
# Clinical significance
KIF1A is associated with hereditary spastic paraparesis.[5]
The website KIF1A.org serves as a resource for patients and care-givers, and provides links to research efforts. | https://www.wikidoc.org/index.php/KIF1A | |
1adacda68030a021ab03836a1ba5e076e2219879 | wikidoc | KIF22 | KIF22
Kinesin-like protein KIF22 is a protein that in humans is encoded by the KIF22 gene.
The protein encoded by this gene is a member of kinesin-like protein family. This family of proteins are microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. The C-terminal half of this protein has been shown to bind DNA. Studies with the Xenopus homolog suggests an essential role in metaphase chromosome alignment and maintenance.
# Interactions
KIF22 has been shown to interact with SIAH1.
# Clinical relevance
Mutations in this gene have been shown to cause developmental disorders such as Spondyloepimetaphyseal dysplasia with joint laxity. | KIF22
Kinesin-like protein KIF22 is a protein that in humans is encoded by the KIF22 gene.[1][2][3]
The protein encoded by this gene is a member of kinesin-like protein family. This family of proteins are microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. The C-terminal half of this protein has been shown to bind DNA. Studies with the Xenopus homolog suggests an essential role in metaphase chromosome alignment and maintenance.[3]
# Interactions
KIF22 has been shown to interact with SIAH1.[4]
# Clinical relevance
Mutations in this gene have been shown to cause developmental disorders such as Spondyloepimetaphyseal dysplasia with joint laxity.[5] | https://www.wikidoc.org/index.php/KIF22 | |
833212c8b00340adc8acca22c87acdbced53419c | wikidoc | KIF23 | KIF23
Kinesin-like protein KIF23 is a protein that in humans is encoded by the KIF23 gene.
# Function
## In cell division
KIF23 (also known as Kinesin-6, CHO1/MKLP1, C. elegans ZEN-4 and Drosophila Pavarotti) is a member of kinesin-like protein family. This family includes microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. This protein has been shown to cross-bridge antiparallel microtubules and drive microtubule movement in vitro. Alternate splicing of this gene results in two transcript variants encoding two different isoforms, better known as CHO1, the larger isoform and MKLP1, the smaller isoform. KIF23 is a plus-end directed motor protein expressed in mitosis, involved in the formation of the cleavage furrow in late anaphase and in cytokinesis. KIF23 is part of the centralspindlin complex that includes PRC1, Aurora B and 14-3-3 which cluster together at the spindle midzone to enable anaphase in dividing cells.
## In neurons
In neuronal development KIF23 is involved in the transport of minus-end distal microtubules into dendrites and is expressed exclusively in cell bodies and dendrites. Knockdown of KIF23 by antisense oligonucleotides and by siRNA both cause a significant increase in axon length and a decrease in dendritic phenotype in neuroblastoma cells and in rat neurons. In differentiating neurons, KIF23 restricts the movement of short microtubules into axons by acting as a "brake" against the driving forces of cytoplasmic dynein. As neurons mature, KIF23 drives minus-end distal microtubules into nascent dendrites contributing to the multi-polar orientation of dendritic microtubules and the formation of their short, fat, tapering morphology.
# Interactions
KIF23 has been shown to interact with:
- ARF3,
- AURKB,
- BIRC6, and
- PRC1.
# Mutation and diseases
KIF23 has been implicated in the formation and proliferation of GL261 gliomas in mouse. | KIF23
Kinesin-like protein KIF23 is a protein that in humans is encoded by the KIF23 gene.[1][2]
# Function
## In cell division
KIF23 (also known as Kinesin-6, CHO1/MKLP1, C. elegans ZEN-4 and Drosophila Pavarotti) is a member of kinesin-like protein family. This family includes microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. This protein has been shown to cross-bridge antiparallel microtubules and drive microtubule movement in vitro. Alternate splicing of this gene results in two transcript variants encoding two different isoforms, better known as CHO1, the larger isoform and MKLP1, the smaller isoform.[2] KIF23 is a plus-end directed motor protein expressed in mitosis, involved in the formation of the cleavage furrow in late anaphase and in cytokinesis.[1][3][4] KIF23 is part of the centralspindlin complex that includes PRC1, Aurora B and 14-3-3 which cluster together at the spindle midzone to enable anaphase in dividing cells.[5][6][7]
## In neurons
In neuronal development KIF23 is involved in the transport of minus-end distal microtubules into dendrites and is expressed exclusively in cell bodies and dendrites.[8][9][10][11][12] Knockdown of KIF23 by antisense oligonucleotides and by siRNA both cause a significant increase in axon length and a decrease in dendritic phenotype in neuroblastoma cells and in rat neurons.[10][11][13] In differentiating neurons, KIF23 restricts the movement of short microtubules into axons by acting as a "brake" against the driving forces of cytoplasmic dynein. As neurons mature, KIF23 drives minus-end distal microtubules into nascent dendrites contributing to the multi-polar orientation of dendritic microtubules and the formation of their short, fat, tapering morphology.[13]
# Interactions
KIF23 has been shown to interact with:
- ARF3,[14]
- AURKB,[6][15][16]
- BIRC6,[17] and
- PRC1.[18]
# Mutation and diseases
KIF23 has been implicated in the formation and proliferation of GL261 gliomas in mouse.[19] | https://www.wikidoc.org/index.php/KIF23 | |
1c8521b5a741522ddeedab854c6db377ef46b35d | wikidoc | KIF3B | KIF3B
Kinesin-like protein KIF3B is a protein that in humans is encoded by the KIF3B gene.
# Function
The protein encoded by this gene forms a heterotrimeric motor complex with kinesin family member 3A and KAP3 (kinesin accessory protein 3) to drive intra-flagellar transport and possibly to aid in chromosome movement during mitosis and meiosis. The encoded protein is a plus end-directed microtubule motor and can interact with the SMC3 subunit of the cohesin complex. In addition, the encoded protein may be involved in the intracellular movement of membranous organelles. The heterotrimeric KIF3B/KIF3A/KAP3 motor protein is a member of the kinesin-2 subfamily of the kinesin superfamily.
# Interactions
KIF3B has been shown to interact with RAB4A.
# Model organisms
Model organisms have been used in the study of KIF3B function. A conditional knockout mouse line called Kif3btm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | KIF3B
Kinesin-like protein KIF3B is a protein that in humans is encoded by the KIF3B gene.[1][2]
# Function
The protein encoded by this gene forms a heterotrimeric motor complex with kinesin family member 3A and KAP3 (kinesin accessory protein 3) to drive intra-flagellar transport and possibly to aid in chromosome movement during mitosis and meiosis. The encoded protein is a plus end-directed microtubule motor and can interact with the SMC3 subunit of the cohesin complex. In addition, the encoded protein may be involved in the intracellular movement of membranous organelles. The heterotrimeric KIF3B/KIF3A/KAP3 motor protein is a member of the kinesin-2 subfamily of the kinesin superfamily.[2][3][4]
# Interactions
KIF3B has been shown to interact with RAB4A.[5]
# Model organisms
Model organisms have been used in the study of KIF3B function. A conditional knockout mouse line called Kif3btm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[6] Male and female animals underwent a standardized phenotypic screen[7] to determine the effects of deletion.[8][9][10][11] Additional screens performed: - In-depth immunological phenotyping[12] | https://www.wikidoc.org/index.php/KIF3B | |
18be37f5c2696be682d5fbc9373d47e900de085e | wikidoc | KLF13 | KLF13
Kruppel-like factor 13, also known as KLF13, is a protein that in humans is encoded by the KLF13 gene.
There is some evidence for KLF13 having a role in obesity. A methylation site, cg07814318, within the first intron of KLF13 has been associated with obesity and orexigenic processes. Ghrelin levels also positively correlated with methylation levels of cg07814318. Moreover, expression levels of KLF13 were decreased and increased in the brains of starved and obese mice, respectively.
# Function
KLF13 belongs to a family of transcription factors that contain 3 classical zinc finger DNA-binding domains consisting of a zinc atom tetrahedrally coordinated by 2 cysteines and 2 histidines (C2H2 motif). These transcription factors bind to GC-rich sequences and related GT and CACCC boxes.
KLF13 was first described as the RANTES factor of late activated T lymphocytes (RFLAT)-1. It regulates the expression of the chemokine RANTES in T lymphocytes. It functions as a lynchpin, inducing a large enhancesome. KLF13 knock-out mice show a defect in lymphocyte survival as KLF13 is a regulator of Bcl-xL expression.
# Interactions
KLF13 has been shown to interact with CREB-binding protein, Heat shock protein 47 and PCAF. | KLF13
Kruppel-like factor 13, also known as KLF13, is a protein that in humans is encoded by the KLF13 gene.[1][2][3]
There is some evidence for KLF13 having a role in obesity. A methylation site, cg07814318, within the first intron of KLF13 has been associated with obesity and orexigenic processes.[4] Ghrelin levels also positively correlated with methylation levels of cg07814318.[4] Moreover, expression levels of KLF13 were decreased and increased in the brains of starved and obese mice, respectively.[4]
# Function
KLF13 belongs to a family of transcription factors that contain 3 classical zinc finger DNA-binding domains consisting of a zinc atom tetrahedrally coordinated by 2 cysteines and 2 histidines (C2H2 motif). These transcription factors bind to GC-rich sequences and related GT and CACCC boxes.[1][5]
KLF13 was first described as the RANTES factor of late activated T lymphocytes (RFLAT)-1.[3] It regulates the expression of the chemokine RANTES in T lymphocytes. It functions as a lynchpin, inducing a large enhancesome. KLF13 knock-out mice show a defect in lymphocyte survival as KLF13 is a regulator of Bcl-xL expression.[3][6][7][8][9][10][11]
# Interactions
KLF13 has been shown to interact with CREB-binding protein,[12] Heat shock protein 47[12] and PCAF.[12] | https://www.wikidoc.org/index.php/KLF13 | |
31cc470e2d86d1c64c88663ec06232d5caee2e85 | wikidoc | KLF14 | KLF14
Krüppel-like factor 14, also known as basic transcription element-binding protein 5 (BTEB5) is a protein that in humans is encoded by the KLF14 gene. The corresponding Klf14 mouse gene is known as Sp6.
# Function
KLF14 is a member of the Krüppel-like factor family of transcription factors. It regulates the transcription of various genes, including TGFβRII (the type II receptor for TGFβ). KLF14 is expressed in many tissues, lacks introns, and is subject to parent-specific expression.
KLF14 appears to be a master regulator of gene expression in adipose tissue.
# Protein structure
Like the other members of the KLF family, KLF14 has three zinc-finger domains near the C-terminus, all three of which are of the classical C2H2 type. In the human, they are at amino acids 195–219, 225–249, and 255–277.
Human KLF14 is 323 amino acids in length, with a molecular weight of 33,124; in the mouse its length is 325.
# Clinical significance
There appears to be a connection between KLF14 and coronary artery disease, hypercholesterolemia and type 2 diabetes. | KLF14
Krüppel-like factor 14, also known as basic transcription element-binding protein 5 (BTEB5) is a protein that in humans is encoded by the KLF14 gene.[1] The corresponding Klf14 mouse gene is known as Sp6.[2]
# Function
KLF14 is a member of the Krüppel-like factor family of transcription factors. It regulates the transcription of various genes, including TGFβRII (the type II receptor for TGFβ).[3] KLF14 is expressed in many tissues,[4] lacks introns, and is subject to parent-specific expression.[5]
KLF14 appears to be a master regulator of gene expression in adipose tissue.[6]
# Protein structure
Like the other members of the KLF family, KLF14 has three zinc-finger domains near the C-terminus, all three of which are of the classical C2H2 type. In the human, they are at amino acids 195–219, 225–249, and 255–277.[7]
Human KLF14 is 323 amino acids in length, with a molecular weight of 33,124;[7] in the mouse its length is 325.[8]
# Clinical significance
There appears to be a connection between KLF14 and coronary artery disease, hypercholesterolemia and type 2 diabetes.[9][10] | https://www.wikidoc.org/index.php/KLF14 | |
b52418768a7b8bb835007ada6c6ce965610471f9 | wikidoc | KLF15 | KLF15
Krüppel-like factor 15 is a protein that in humans is encoded by the KLF15 gene in the Krüppel-like factor family. Its former designation KKLF stands for kidney-enriched Krüppel-like factor.
# Expression
Activated glucocorticoid receptor upregulates the expression of KLF15.
KLF15 is increased by fasting and decreased by feeding and insulin via PI3K signalling. KLF15 was increased by glucocorticoid signalling and was also increased by inhibition of PI3K. Insulin and its counteracting hormones regulate the hepatic expression of KLF15. Forced expression of KLF15 in cultured hepatocytes increased both the expression and the promoter activity of the gene for phosphoenolpyruvate carboxykinase (PEPCK).
KLF15 levels in both humans and mice increase two to three times in response to exercise and control the ability of muscle tissue to burn fat and generate force. Deficiency of the KLF15 gene in mice was shown to prevent the efficient burning of fat and prevented mice from sustaining aerobic exercise.
KLF15 in adipose tissue is down-regulated in obese mice. aP2-KLF15 Tg mice which overexpress KLF15 manifest insulin resistance and are resistant to the development of obesity induced by maintenance on a high fat diet. However, they also exhibit improved glucose tolerance as a result of enhanced insulin secretion. The enhancement of insulin secretion resulted from down-regulation of stearoyl-CoA desaturase-1 (SCD1) in white adipose tissue and a consequent reduced level of oxidative stress. This is supported by the findings that restoration of SCD1 expression in WAT of aP2-KLF15 Tg mice exhibited increased oxidative stress in WAT, reduced insulin secretion with hyperglycemia. The data indicates an example of cross talk between white adipose tissue and pancreatic β cells mediated through modulation of oxidative stress.
Using deletion and mutation analysis, EMSA and ChIP, demonstrated that USF1 and Spl can bind to E-box in-80 to-45 and GC-box in-189 to-155 in the KLF15 promoter respectively, thus regulating the transcription of KLF15 gene.
# Gene regulation
KLF15 binding site in the HSD17B5 promoter leading to the upregulation of testosterone production. In addition KLF15 overexpression in combination with insulin, glucocorticoid, and cAMP stimulated adipogenesis in H295R cells. In silico and RT-PCR analyses showed that the KLF15 gene promoter undergoes alternative splicing in a tissue-specific manner
KLF15 is a strong and direct activator of BMPER expression which is inhibited by SP1. BMPER is inhibited by endothelin-1, which may be mediated by endothelin inhibition of KLF15.
The LRP5 promoter has a KLF15 binding site.
KLF15 specifically interacts with MEF2A and synergistically activates the GLUT4 promoter via an intact KLF15-binding site proximal to the MEF2A site. Cardiac and skeletal muscle expressed miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes.
Transforming growth factor-beta1 (TGFbeta1) strongly reduces KLF15 expression. Adenoviral overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF expression in neonatal rat ventricular fibroblasts. Hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. KLF15 is implicated as a novel negative regulator of CTGF expression and cardiac fibrosis.
KLF15 inhibits myocardin. TGFbeta mediated activation of p38 MAPK decreases KLF15 permitting the upreg of myocardin and stimulate the expression of serum response factor target genes, such as atrial natriuretic factor eventually leading to left ventricular hypertrophy which often progresses to heart failure.
The combination of KLF15 and Sp1 resulted in a synergistic activation of the acetyl-CoA synthetase 2 (AceCS2) promoter. AceCS2 produces acetyl-CoA for oxidation through the citric acid cycle in the mitochondrial matrix. Fasting upregulated KLF15 which upregulated AceCS2.
Progesterone receptor-mediated induction of Krüppel-like factor 15 (KLF15), which can bind to GC-rich DNA within the E2F1 promoter, is required for maximal induction of E2F1 expression by progestins.
KLF15 may function as an inhibitor of cardiac hypertrophycan by the inhibition of GATA4 and MEF2.
REDD1 and KLF15 are direct target genes of the glucocorticoid receptor (GR) in skeletal muscle. KLF15 inhibits mTOR activity via a distinct mechanism involving BCAT2 gene activation. KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1 and SMuRF1 genes and negatively modulates myofiber size.
Two kidney-specific CLC chloride channels, CLC-K1 and CLC-K2, are transcriptionally regulated on a tissue-specific basis. KLF15 (KKLF) is abundantly expressed in the liver, kidney, heart, and skeletal muscle. In the kidney, KKLF protein was localized in interstitial cells, mesangial cells, and nephron segments where CLC-K1 and CLC-K2 were not expressed. KKLF and MAZ proteins exhibited sequence-specific binding to the CLC-K1 GA element. MAZ had a strong activating effect on CLC-K1 gene transcription but KKLF coexpression with MAZ appeared to block the activating effect of MAZ.
# Clinical significance
KLF15 plays an important role in regulation of the expression of genes for gluconeogenic and amino acid-degrading enzymes and that the inhibitory effect of metformin on gluconeogenesis is mediated at least in part by downregulation of KLF15 and consequent attenuation of the expression of such genes.
Klf15 concentrations are markedly reduced in failing human hearts and in human aortic aneurysm tissues. Mice deficient in Klf15 develop heart failure and aortic aneurysms in a p53-dependent and p300 acetyltransferase-dependent fashion. KLF15 activation inhibits p300-mediated acetylation of p53. Conversely, Klf15 deficiency leads to hyperacetylation of p53 in the heart and aorta, a finding that is recapitulated in human tissues. Finally, Klf15-deficient mice are rescued by p53 deletion or p300 inhibition. These findings highlight a molecular perturbation common to the pathobiology of heart failure and aortic aneurysm formation and suggest that manipulation of KLF15 function may be a productive approach to treat these morbid diseases.
The expression of the KLF15 gene is markedly up-regulated during the differentiation of 3T3-L1 preadipocytes into adipocytes. Ectopic expression of KLF15 in NIH 3T3 or C2C12 cells triggered both lipid accumulation and the expression of PPAR-γ in the presence of inducers of adipocyte differentiation. Ectopic expression of C/EBPbeta, C/EBPdelta, or C/EBPalpha in 3T3 cells also elicited the expression of KLF15 in the presence of inducers of adipocyte differentiation. KLF15 and C/EBPalpha act synergistically to increase the activity of the PPARgamma2 gene promoter in 3T3-L1 adipocytes demonstrating that KLF15 plays an essential role in adipogenesis in 3T3-L1 cells through its regulation of PPAR gamma expression.
The minimal transactivation domain of erythroid Krüppel-like factor EKLFTAD) has two functional subdomains EKLFTAD1 and EKLFTAD2 of which EKLFTAD2 is conserved in KLF15. EKLFTAD2 binds the amino-terminal PH domain of the Tfb1/p62 subunit of TFIIH (Tfb1PH/p62PH) and four domains of CREB-binding protein/p300.
KLF15 is a novel transcriptional activator for hepatitis B virus core and surface promoters. It is possible that KLF15 may serve as a potential therapeutic target to reduce HBV gene expression and viral replication.
Circadian control of KLF15 expression controls the expression of kChIP2 which affects how potassium flows out of heart cells. Too much or too little of KLF15 or kChIP2 may result in arrhythmias.
In rodents KLF15 appears to control the actions of estradiol and progesterone in the endometrium by inhibiting the production of MCM2, a protein involved in DNA synthesis raising the possibility of preventing or treating endometrial and breast cancer and other diseases related to estrogen by promoting the action of KLF15. | KLF15
Krüppel-like factor 15 is a protein that in humans is encoded by the KLF15 gene[1] in the Krüppel-like factor family. Its former designation KKLF stands for kidney-enriched Krüppel-like factor.[2]
# Expression
Activated glucocorticoid receptor upregulates the expression of KLF15.[3]
KLF15 is increased by fasting and decreased by feeding and insulin via PI3K signalling. KLF15 was increased by glucocorticoid signalling and was also increased by inhibition of PI3K. Insulin and its counteracting hormones regulate the hepatic expression of KLF15. Forced expression of KLF15 in cultured hepatocytes increased both the expression and the promoter activity of the gene for phosphoenolpyruvate carboxykinase (PEPCK).[4]
KLF15 levels in both humans and mice increase two to three times in response to exercise and control the ability of muscle tissue to burn fat and generate force. Deficiency of the KLF15 gene in mice was shown to prevent the efficient burning of fat and prevented mice from sustaining aerobic exercise.[5]
KLF15 in adipose tissue is down-regulated in obese mice. aP2-KLF15 Tg mice which overexpress KLF15 manifest insulin resistance and are resistant to the development of obesity induced by maintenance on a high fat diet. However, they also exhibit improved glucose tolerance as a result of enhanced insulin secretion. The enhancement of insulin secretion resulted from down-regulation of stearoyl-CoA desaturase-1 (SCD1) in white adipose tissue and a consequent reduced level of oxidative stress. This is supported by the findings that restoration of SCD1 expression in WAT of aP2-KLF15 Tg mice exhibited increased oxidative stress in WAT, reduced insulin secretion with hyperglycemia. The data indicates an example of cross talk between white adipose tissue and pancreatic β cells mediated through modulation of oxidative stress.[6]
Using deletion and mutation analysis, EMSA and ChIP, demonstrated that USF1 and Spl can bind to E-box in-80 to-45 and GC-box in-189 to-155 in the KLF15 promoter respectively, thus regulating the transcription of KLF15 gene.[7]
# Gene regulation
KLF15 binding site in the HSD17B5 promoter leading to the upregulation of testosterone production. In addition KLF15 overexpression in combination with insulin, glucocorticoid, and cAMP stimulated adipogenesis in H295R cells. In silico and RT-PCR analyses showed that the KLF15 gene promoter undergoes alternative splicing in a tissue-specific manner [8]
KLF15 is a strong and direct activator of BMPER expression which is inhibited by SP1. BMPER is inhibited by endothelin-1, which may be mediated by endothelin inhibition of KLF15.[9]
The LRP5 promoter has a KLF15 binding site.[10]
KLF15 specifically interacts with MEF2A and synergistically activates the GLUT4 promoter via an intact KLF15-binding site proximal to the MEF2A site. Cardiac and skeletal muscle expressed miR-133 regulates the expression of GLUT4 by targeting KLF15 and is involved in metabolic control in cardiomyocytes.[11][12]
Transforming growth factor-beta1 (TGFbeta1) strongly reduces KLF15 expression. Adenoviral overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF expression in neonatal rat ventricular fibroblasts. Hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. KLF15 is implicated as a novel negative regulator of CTGF expression and cardiac fibrosis.[13]
KLF15 inhibits myocardin. TGFbeta mediated activation of p38 MAPK decreases KLF15 permitting the upreg of myocardin and stimulate the expression of serum response factor target genes, such as atrial natriuretic factor eventually leading to left ventricular hypertrophy which often progresses to heart failure.[14]
The combination of KLF15 and Sp1 resulted in a synergistic activation of the acetyl-CoA synthetase 2 (AceCS2) promoter. AceCS2 produces acetyl-CoA for oxidation through the citric acid cycle in the mitochondrial matrix. Fasting upregulated KLF15 which upregulated AceCS2.[15]
Progesterone receptor-mediated induction of Krüppel-like factor 15 (KLF15), which can bind to GC-rich DNA within the E2F1 promoter, is required for maximal induction of E2F1 expression by progestins.[16]
KLF15 may function as an inhibitor of cardiac hypertrophycan by the inhibition of GATA4 and MEF2.[17]
REDD1 and KLF15 are direct target genes of the glucocorticoid receptor (GR) in skeletal muscle. KLF15 inhibits mTOR activity via a distinct mechanism involving BCAT2 gene activation. KLF15 upregulates the expression of the E3 ubiquitin ligases atrogin-1 and SMuRF1 genes and negatively modulates myofiber size.[18]
Two kidney-specific CLC chloride channels, CLC-K1 and CLC-K2, are transcriptionally regulated on a tissue-specific basis. KLF15 (KKLF) is abundantly expressed in the liver, kidney, heart, and skeletal muscle. In the kidney, KKLF protein was localized in interstitial cells, mesangial cells, and nephron segments where CLC-K1 and CLC-K2 were not expressed. KKLF and MAZ proteins exhibited sequence-specific binding to the CLC-K1 GA element. MAZ had a strong activating effect on CLC-K1 gene transcription but KKLF coexpression with MAZ appeared to block the activating effect of MAZ.[19]
# Clinical significance
KLF15 plays an important role in regulation of the expression of genes for gluconeogenic and amino acid-degrading enzymes and that the inhibitory effect of metformin on gluconeogenesis is mediated at least in part by downregulation of KLF15 and consequent attenuation of the expression of such genes.[20]
Klf15 concentrations are markedly reduced in failing human hearts and in human aortic aneurysm tissues. Mice deficient in Klf15 develop heart failure and aortic aneurysms in a p53-dependent and p300 acetyltransferase-dependent fashion. KLF15 activation inhibits p300-mediated acetylation of p53. Conversely, Klf15 deficiency leads to hyperacetylation of p53 in the heart and aorta, a finding that is recapitulated in human tissues. Finally, Klf15-deficient mice are rescued by p53 deletion or p300 inhibition. These findings highlight a molecular perturbation common to the pathobiology of heart failure and aortic aneurysm formation and suggest that manipulation of KLF15 function may be a productive approach to treat these morbid diseases.[21]
The expression of the KLF15 gene is markedly up-regulated during the differentiation of 3T3-L1 preadipocytes into adipocytes. Ectopic expression of KLF15 in NIH 3T3 or C2C12 cells triggered both lipid accumulation and the expression of PPAR-γ in the presence of inducers of adipocyte differentiation. Ectopic expression of C/EBPbeta, C/EBPdelta, or C/EBPalpha in 3T3 cells also elicited the expression of KLF15 in the presence of inducers of adipocyte differentiation. KLF15 and C/EBPalpha act synergistically to increase the activity of the PPARgamma2 gene promoter in 3T3-L1 adipocytes demonstrating that KLF15 plays an essential role in adipogenesis in 3T3-L1 cells through its regulation of PPAR gamma expression.[22]
The minimal transactivation domain of erythroid Krüppel-like factor EKLFTAD) has two functional subdomains EKLFTAD1 and EKLFTAD2 of which EKLFTAD2 is conserved in KLF15. EKLFTAD2 binds the amino-terminal PH domain of the Tfb1/p62 subunit of TFIIH (Tfb1PH/p62PH) and four domains of CREB-binding protein/p300.[23]
KLF15 is a novel transcriptional activator for hepatitis B virus core and surface promoters. It is possible that KLF15 may serve as a potential therapeutic target to reduce HBV gene expression and viral replication.[24]
Circadian control of KLF15 expression controls the expression of kChIP2 which affects how potassium flows out of heart cells. Too much or too little of KLF15 or kChIP2 may result in arrhythmias.[25]
In rodents KLF15 appears to control the actions of estradiol and progesterone in the endometrium by inhibiting the production of MCM2, a protein involved in DNA synthesis raising the possibility of preventing or treating endometrial and breast cancer and other diseases related to estrogen by promoting the action of KLF15.[26] | https://www.wikidoc.org/index.php/KLF15 | |
1ff98c2eee79f44ac91bc4d4bf75fc16aeef55b5 | wikidoc | KLRC2 | KLRC2
NKG2-C type II integral membrane protein is a protein that in humans is encoded by the KLRC2 gene.
# Function
Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. NK cells preferentially express several calcium-dependent (C-type) lectins, which have been implicated in the regulation of NK cell function. The group, designated KLRC (NKG2) are expressed primarily in natural killer (NK) cells and encodes a family of transmembrane proteins characterized by a type II membrane orientation (extracellular C terminus) and the presence of a C-type lectin domain. The KLRC (NKG2) gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed on NK cells. KLRC2 alternative splice variants have been described but their full-length nature has not been determined.
# Interactions
KLRC2 has been shown to interact with KLRD1.
The binding of this CD94/NKG2C heterodimer to its cellular ligand HLA-E has been shown to drive the expansion of a subset of Natural Killer (NK) cells in response to viral infections. | KLRC2
NKG2-C type II integral membrane protein is a protein that in humans is encoded by the KLRC2 gene.[1][2]
# Function
Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. NK cells preferentially express several calcium-dependent (C-type) lectins, which have been implicated in the regulation of NK cell function. The group, designated KLRC (NKG2) are expressed primarily in natural killer (NK) cells and encodes a family of transmembrane proteins characterized by a type II membrane orientation (extracellular C terminus) and the presence of a C-type lectin domain. The KLRC (NKG2) gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed on NK cells. KLRC2 alternative splice variants have been described but their full-length nature has not been determined.[2]
# Interactions
KLRC2 has been shown to interact with KLRD1.[3][4]
The binding of this CD94/NKG2C heterodimer to its cellular ligand HLA-E has been shown to drive the expansion of a subset of Natural Killer (NK) cells in response to viral infections.[5] | https://www.wikidoc.org/index.php/KLRC2 | |
2466fa790bc3c7397850c9239fc57242fad9ddc2 | wikidoc | KLRD1 | KLRD1
CD94 (Cluster of Differentiation 94), also known as killer cell lectin-like receptor subfamily D, member 1 (KLRD1) is a human gene.
The protein encoded by CD94 gene is a lectin, cluster of differentiation and a receptor that is involved in cell signaling and is expressed on the surface of natural killer cells in the innate immune system. CD94 pairs with the NKG2 molecule as a heterodimer. The CD94/NKG2 complex, on the surface of natural killer cells interacts with Human Leukocyte Antigen (HLA)-E on target cells.
# Function
Natural killer (NK) cells are a distinct lineage of lymphocytes that mediate cytotoxic activity and secrete cytokines upon immune stimulation. Several genes of the C-type lectin superfamily, including members of the NKG2 family, are expressed by NK cells and may be involved in the regulation of NK cell function. KLRD1 (CD94) is an antigen preferentially expressed on NK cells and is classified as a type II membrane protein because it has an external C terminus. KLRD1 has two alternatively spliced variants that differ in the presence or absence of exon 2 sequence.
# Interactions
KLRD1 has been shown to interact with KLRC2. | KLRD1
CD94 (Cluster of Differentiation 94), also known as killer cell lectin-like receptor subfamily D, member 1 (KLRD1) is a human gene.[1]
The protein encoded by CD94 gene is a lectin, cluster of differentiation and a receptor that is involved in cell signaling and is expressed on the surface of natural killer cells in the innate immune system. CD94 pairs with the NKG2 molecule as a heterodimer. The CD94/NKG2 complex, on the surface of natural killer cells interacts with Human Leukocyte Antigen (HLA)-E on target cells.
# Function
Natural killer (NK) cells are a distinct lineage of lymphocytes that mediate cytotoxic activity and secrete cytokines upon immune stimulation. Several genes of the C-type lectin superfamily, including members of the NKG2 family, are expressed by NK cells and may be involved in the regulation of NK cell function. KLRD1 (CD94) is an antigen preferentially expressed on NK cells and is classified as a type II membrane protein because it has an external C terminus. KLRD1 has two alternatively spliced variants that differ in the presence or absence of exon 2 sequence.[1]
# Interactions
KLRD1 has been shown to interact with KLRC2.[2][3] | https://www.wikidoc.org/index.php/KLRD1 | |
fd3b789bcba55bd77215b60f99aa4350217d9167 | wikidoc | KLRG1 | KLRG1
Killer cell lectin-like receptor subfamily G member 1 is a protein that in humans is encoded by the KLRG1 gene.
# Function
Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. The protein encoded by this gene belongs to the killer cell lectin-like receptor (KLR) family, which is a group of transmembrane proteins preferentially expressed in NK cells. Studies in mice suggested that the expression of this gene may be regulated by MHC class I molecules.
KLRG1 is a lymphocyte co-inhibitory, or immune checkpoint, receptor expressed predominantly on late-differentiated effector and effector memory CD8+ T and NK cells. It’s ligands are E-cadherin and N-cadherin with similar affinities, respective markers of epithelial and mesenchymal cells. Targeting of other co-inhibitory receptors for applications in oncology has gained widespread interest (e.g., CTLA-4, PD-1, and its ligand PD-L1). Unlike the obvious enhanced immune activation present in CTLA-4 and PD-1 gene knockout mice, KLRG1 knockout mice initially were found to have no abnormal features, though were subsequently found to have enhanced immunity in a tuberculosis challenge model.
The characterization of KLRG1 as a “senescent” marker, but other co-inhibitory receptors as “exhaustion” markers, has contributed to relatively fewer studies on this molecule. | KLRG1
Killer cell lectin-like receptor subfamily G member 1 is a protein that in humans is encoded by the KLRG1 gene.[1][2][3][4][5]
# Function
Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. The protein encoded by this gene belongs to the killer cell lectin-like receptor (KLR) family, which is a group of transmembrane proteins preferentially expressed in NK cells. Studies in mice suggested that the expression of this gene may be regulated by MHC class I molecules.[5]
KLRG1 is a lymphocyte co-inhibitory, or immune checkpoint, receptor expressed predominantly on late-differentiated effector and effector memory CD8+ T and NK cells. It’s ligands are E-cadherin and N-cadherin with similar affinities,[6] respective markers of epithelial and mesenchymal cells.[7] Targeting of other co-inhibitory receptors for applications in oncology has gained widespread interest[8][9][10] (e.g., CTLA-4, PD-1, and its ligand PD-L1). Unlike the obvious enhanced immune activation present in CTLA-4 and PD-1 gene knockout mice,[11][12] KLRG1 knockout mice initially were found to have no abnormal features,[13] though were subsequently found to have enhanced immunity in a tuberculosis challenge model.[14]
The characterization of KLRG1 as a “senescent” marker, but other co-inhibitory receptors as “exhaustion” markers,[15][16][17] has contributed to relatively fewer studies on this molecule. | https://www.wikidoc.org/index.php/KLRG1 | |
bbf55635acef1bbc3cd65924b59dde2aec038094 | wikidoc | KMT2D | KMT2D
Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2F (or SET1A), and KMT2G (or SET1B). KMT2D is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues. The protein co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development. It also plays critical roles in regulating cell fate transition, metabolism, and tumor suppression. Mutations in KMT2D have been associated with Kabuki Syndrome, congenital heart disease, and various forms of cancer.
# Structure
## Gene
In mice, KMT2D is coded by the Kmt2d gene located on chromosome 15F1. Its transcript is 19,823 base pairs long and contains 55 exons and 54 introns. In humans, KMT2D is coded by the KMT2D gene located on chromosome 12q13.12. Its transcript is 19,419 base pairs long and contains 54 exons and 53 introns.
## Protein
KMT2D is homologous to Trithorax-related (Trr), which is a Trithorax-group protein. The mouse and human KMT2D proteins are 5,588 and 5,537 amino acids in length, respectively. Both species of the protein weigh about 600 kDa. KMT2D contains an enzymatically active C-terminal SET domain that is responsible for its methyltransferase activity and maintaining protein stability in cells. Near the SET domain are a plant homeotic domain (PHD) and FY-rich N/C-terminal (FYRN and FYRC) domains. The protein also contains six N-terminal PHDs, a high mobility group (HMG-I), and nine nuclear receptor interacting motifs (LXXLLs). It was shown that amino acids Y5426 and Y5512 are critical for the enzymatic activity of human KMT2D in vitro. In addition, mutation of Y5477 in mouse KMT2D, which corresponds to Y5426 in human KMT2D, resulted in the inactivation of KMT2D's enzymatic activity in embryonic stem cells. Depletion of cellular H3K4 methylation reduces KMT2D levels, indicating that the protein's stability could be regulated by cellular H3K4 methylation.
## Protein complex
Several components of the KMT2D complex were first purified in 2003, and then the entire complex was identified in 2007. Along with KMT2D, the complex also contains ASH2L, RbBP5, WDR5, DPY30, NCOA6, UTX (also known as KDM6A), PA1, and PTIP. WDR5, RbBP5, ASH2L, and DPY30 form the four-subunit sub-complex WRAD, which is critical for H3K4 methyltransferase activity in all mammalian Set1-like histone methyltransferase complexes. WDR5 binds directly with FYRN/FYRC domains of C-terminal SET domain-containing fragments of human KMT2C and KMT2D. UTX, the complex’s H3K27 demethylase, PTIP, and PA1 are subunits that are unique to KMT2C and KMT2D. KMT2D acts as a scaffold protein within the complex; absence of KMT2D results in destabilization of UTX and collapse of the complex in cells.
# Enhancer regulation
KMT2D is a major enhancer mono-methyltransferase and has partial functional redundancy with KMT2C. The protein selectively binds enhancer regions based on type of cell and stage of differentiation. During differentiation, lineage determining transcription factors recruit KMT2D to establish cell-type specific enhancers. For example, CCAAT/enhancer-binding protein β (C/EBPβ), an early adipogenic transcription factor, recruits and requires KMT2D to establish a subset of adipogenic enhancers during adipogenesis. Depletion of KMT2D prior to differentiation prevents the accumulation of H3K4 mono-methylation (H3K4me1), H3K27 acetylation, the transcriptional coactivator Mediator, and RNA polymerase II on enhancers, resulting in severe defects in gene expression and cell differentiation. KMT2C and KMT2D also identify super-enhancers and are required for formation of super-enhancers during cell differentiation. Mechanistically, KMT2C and KMT2D are required for the binding of H3K27 acetyltransferases CREB-binding protein (CBP) and/or p300 on enhancers, enhancer activation, and enhancer-promotor looping prior to gene transcription. The KMT2C and KMT2D proteins, rather than the KMT2C and KMT2D-mediated H3K4me1, control p300 recruitment to enhancers, enhancer activation, and transcription from promoters in embryonic stem cells.
# Functions
## Development
Whole-body knockout of Kmt2d in mice results in early embryonic lethality. Targeted knockout of Kmt2d in precursors cells of brown adipocytes and myocytes results in decreases in brown adipose tissue and muscle mass in mice, indicating that KMT2D is required for adipose and muscle tissue development. In the hearts of mice, a single copy of the Kmt2d gene is sufficient for normal heart development. Complete loss of Kmt2d in cardiac precursors and myocardium leads to severe cardiac defects and early embryonic lethality. KMT2D mediated mono- and di-methylation is required for maintaining necessary gene expression programs during heart development. Knockout studies in mice also show that KMT2D is required for proper B-cell development.
## Cell fate transition
KMT2D is partially functionally redundant with KMT2C and is required for cell differentiation in culture. KMT2D regulates the induction of adipogenic and myogenic genes and is required for cell-type specific gene expression during differentiation. KMT2C and KMT2D are essential for adipogenesis and myogenesis. Similar functions are seen in neuronal and osteoblast differentiation. KMT2D facilitates cell fate transition by priming enhancers (through H3K4me1) for p300-mediated activation. For p300 to bind the enhancer, the physical presence of KMT2D, and not just the KMT2D-mediated H3K4me1, is required. However, KMT2D is dispensable for maintaining embryonic stem cell and somatic cell identity.
## Metabolism
KMT2D is partially functionally redundant with KMT2C in the liver as well. Heterozygous Kmt2d+/- mice exhibit enhanced glucose tolerance and insulin sensitivity and increased serum bile acid. KMT2C and KMT2D are significant epigenetic regulators of the hepatic circadian clock and are co-activators of the circadian transcription factors retinoid-related orphan receptor (ROR)-α and -γ. In mice, KMT2D also acts as a coactivator of PPARγ within the liver to direct over-nutrition induced steatosis. Heterozygous Kmt2d+/- mice exhibit resistance to over-nutrition induced hepatic steatosis.
## Tumor suppression
KMT2C and KMT2D along with NCOA6 act as coactivators of p53, a well-established tumor suppressor and transcription factor, and are necessary for endogenous expression of p53 in response to doxorubicin, a DNA damaging agent. KMT2C and KMT2D have also been implicated with tumor suppressor roles in acute myeloid leukemia, follicular lymphoma, and diffuse large B cell lymphoma. Knockout of Kmt2d in mice negatively affects the expression of tumor suppressor genes TNFAIP3, SOCS3, and TNFRSF14.
Conversely, KMT2D deficiency in several breast and colon cancer cell lines leads to reduced proliferation. Increased KMT2D was shown to facilitate chromatin opening and recruitment of transcription factors, including estrogen receptor (ER), in ER-positive breast cancer cells. Thus, KMT2D may have diverse effects on tumor suppression in different cell types.
# Clinical significance
Loss of function mutations in KMT2D, also known as MLL2 in humans, have been identified in Kabuki syndrome, with mutational occurrence rates between 56% and 75%. Congenital heart disease has been associated with an excess of mutations in genes that regulate H3K4 methylation, including KMT2D.
Frameshift and nonsense mutations in the SET and PHD domains affect 37% and 60%, respectively, of the total KMT2D mutations in cancers. Cancers with somatic mutations in KMT2D occur most commonly in the brain, lymph nodes, blood, lungs, large intestine, and endometrium. These cancers include medulloblastoma, pheochromocytoma, non-Hodgkin lymphomas,, cutaneous T-cell lymphoma, Sézary syndrome, bladder, lung, and endometrial carcinomas, esophageal squamous cell carcinoma, pancreatic cancer, and prostate cancer.
# Notes | KMT2D
Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase.[1] It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2F (or SET1A), and KMT2G (or SET1B). KMT2D is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues.[2] The protein co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development.[1] It also plays critical roles in regulating cell fate transition,[1][3][4][5] metabolism,[6][7] and tumor suppression.[8][9][10][11] Mutations in KMT2D have been associated with Kabuki Syndrome,[12] congenital heart disease,[13] and various forms of cancer.[14]
# Structure
## Gene
In mice, KMT2D is coded by the Kmt2d gene located on chromosome 15F1. Its transcript is 19,823 base pairs long and contains 55 exons and 54 introns.[15] In humans, KMT2D is coded by the KMT2D gene located on chromosome 12q13.12. Its transcript is 19,419 base pairs long and contains 54 exons and 53 introns.[16]
## Protein
KMT2D is homologous to Trithorax-related (Trr), which is a Trithorax-group protein.[17] The mouse and human KMT2D proteins are 5,588 and 5,537 amino acids in length, respectively. Both species of the protein weigh about 600 kDa.[15][16] KMT2D contains an enzymatically active C-terminal SET domain that is responsible for its methyltransferase activity and maintaining protein stability in cells.[18] Near the SET domain are a plant homeotic domain (PHD) and FY-rich N/C-terminal (FYRN and FYRC) domains. The protein also contains six N-terminal PHDs, a high mobility group (HMG-I), and nine nuclear receptor interacting motifs (LXXLLs).[14] It was shown that amino acids Y5426 and Y5512 are critical for the enzymatic activity of human KMT2D in vitro.[19] In addition, mutation of Y5477 in mouse KMT2D, which corresponds to Y5426 in human KMT2D, resulted in the inactivation of KMT2D's enzymatic activity in embryonic stem cells.[20] Depletion of cellular H3K4 methylation reduces KMT2D levels, indicating that the protein's stability could be regulated by cellular H3K4 methylation.[19]
## Protein complex
Several components of the KMT2D complex were first purified in 2003,[21] and then the entire complex was identified in 2007.[22][23][24][25] Along with KMT2D, the complex also contains ASH2L, RbBP5, WDR5, DPY30, NCOA6, UTX (also known as KDM6A), PA1, and PTIP. WDR5, RbBP5, ASH2L, and DPY30 form the four-subunit sub-complex WRAD, which is critical for H3K4 methyltransferase activity in all mammalian Set1-like histone methyltransferase complexes.[26] WDR5 binds directly with FYRN/FYRC domains of C-terminal SET domain-containing fragments of human KMT2C and KMT2D.[22] UTX, the complex’s H3K27 demethylase, PTIP, and PA1 are subunits that are unique to KMT2C and KMT2D.[22][27][28] KMT2D acts as a scaffold protein within the complex; absence of KMT2D results in destabilization of UTX and collapse of the complex in cells.[1][19]
# Enhancer regulation
KMT2D is a major enhancer mono-methyltransferase and has partial functional redundancy with KMT2C.[1][3] The protein selectively binds enhancer regions based on type of cell and stage of differentiation. During differentiation, lineage determining transcription factors recruit KMT2D to establish cell-type specific enhancers. For example, CCAAT/enhancer-binding protein β (C/EBPβ), an early adipogenic transcription factor, recruits and requires KMT2D to establish a subset of adipogenic enhancers during adipogenesis. Depletion of KMT2D prior to differentiation prevents the accumulation of H3K4 mono-methylation (H3K4me1), H3K27 acetylation, the transcriptional coactivator Mediator, and RNA polymerase II on enhancers, resulting in severe defects in gene expression and cell differentiation.[1] KMT2C and KMT2D also identify super-enhancers and are required for formation of super-enhancers during cell differentiation.[29] Mechanistically, KMT2C and KMT2D are required for the binding of H3K27 acetyltransferases CREB-binding protein (CBP) and/or p300 on enhancers, enhancer activation, and enhancer-promotor looping prior to gene transcription.[1][29] The KMT2C and KMT2D proteins, rather than the KMT2C and KMT2D-mediated H3K4me1, control p300 recruitment to enhancers, enhancer activation, and transcription from promoters in embryonic stem cells.[3]
# Functions
## Development
Whole-body knockout of Kmt2d in mice results in early embryonic lethality.[1] Targeted knockout of Kmt2d in precursors cells of brown adipocytes and myocytes results in decreases in brown adipose tissue and muscle mass in mice, indicating that KMT2D is required for adipose and muscle tissue development.[1] In the hearts of mice, a single copy of the Kmt2d gene is sufficient for normal heart development.[30] Complete loss of Kmt2d in cardiac precursors and myocardium leads to severe cardiac defects and early embryonic lethality. KMT2D mediated mono- and di-methylation is required for maintaining necessary gene expression programs during heart development. Knockout studies in mice also show that KMT2D is required for proper B-cell development.[8]
## Cell fate transition
KMT2D is partially functionally redundant with KMT2C and is required for cell differentiation in culture.[1][3] KMT2D regulates the induction of adipogenic and myogenic genes and is required for cell-type specific gene expression during differentiation. KMT2C and KMT2D are essential for adipogenesis and myogenesis.[1] Similar functions are seen in neuronal and osteoblast differentiation.[4][5] KMT2D facilitates cell fate transition by priming enhancers (through H3K4me1) for p300-mediated activation. For p300 to bind the enhancer, the physical presence of KMT2D, and not just the KMT2D-mediated H3K4me1, is required. However, KMT2D is dispensable for maintaining embryonic stem cell and somatic cell identity.[3]
## Metabolism
KMT2D is partially functionally redundant with KMT2C in the liver as well. Heterozygous Kmt2d+/- mice exhibit enhanced glucose tolerance and insulin sensitivity and increased serum bile acid.[6] KMT2C and KMT2D are significant epigenetic regulators of the hepatic circadian clock and are co-activators of the circadian transcription factors retinoid-related orphan receptor (ROR)-α and -γ.[6] In mice, KMT2D also acts as a coactivator of PPARγ within the liver to direct over-nutrition induced steatosis. Heterozygous Kmt2d+/- mice exhibit resistance to over-nutrition induced hepatic steatosis.[7]
## Tumor suppression
KMT2C and KMT2D along with NCOA6 act as coactivators of p53, a well-established tumor suppressor and transcription factor, and are necessary for endogenous expression of p53 in response to doxorubicin, a DNA damaging agent.[9] KMT2C and KMT2D have also been implicated with tumor suppressor roles in acute myeloid leukemia, follicular lymphoma, and diffuse large B cell lymphoma.[8][10][11] Knockout of Kmt2d in mice negatively affects the expression of tumor suppressor genes TNFAIP3, SOCS3, and TNFRSF14.[11]
Conversely, KMT2D deficiency in several breast and colon cancer cell lines leads to reduced proliferation.[31][32][33] Increased KMT2D was shown to facilitate chromatin opening and recruitment of transcription factors, including estrogen receptor (ER), in ER-positive breast cancer cells.[34] Thus, KMT2D may have diverse effects on tumor suppression in different cell types.
# Clinical significance
Loss of function mutations in KMT2D, also known as MLL2 in humans, have been identified in Kabuki syndrome,[12] with mutational occurrence rates between 56% and 75%.[35][36][37] Congenital heart disease has been associated with an excess of mutations in genes that regulate H3K4 methylation, including KMT2D.[13]
Frameshift and nonsense mutations in the SET and PHD domains affect 37% and 60%, respectively, of the total KMT2D mutations in cancers.[14] Cancers with somatic mutations in KMT2D occur most commonly in the brain, lymph nodes, blood, lungs, large intestine, and endometrium.[14] These cancers include medulloblastoma,[38][39][40] pheochromocytoma,[41] non-Hodgkin lymphomas,[42], cutaneous T-cell lymphoma, Sézary syndrome,[43] bladder, lung, and endometrial carcinomas,[44] esophageal squamous cell carcinoma,[45][46][47] pancreatic cancer,[48] and prostate cancer.[49]
# Notes | https://www.wikidoc.org/index.php/KMT2D | |
b594dff280f8bc4d8c078f581cacb0217102c5dc | wikidoc | KRT31 | KRT31
Keratin, type I cuticular Ha1 is a protein that in humans is encoded by the KRT31 gene.
# Function
The protein encoded by this gene is a member of the keratin gene family. As a type I hair keratin, it is an acidic protein which heterodimerizes with type II keratins to form hair and nails. The type I hair keratins are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription.
# Model organisms
Model organisms have been used in the study of KRT31 function. A conditional knockout mouse line called Krt31tm1e(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | KRT31
Keratin, type I cuticular Ha1 is a protein that in humans is encoded by the KRT31 gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the keratin gene family. As a type I hair keratin, it is an acidic protein which heterodimerizes with type II keratins to form hair and nails. The type I hair keratins are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription.[3]
# Model organisms
Model organisms have been used in the study of KRT31 function. A conditional knockout mouse line called Krt31tm1e(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[4] Male and female animals underwent a standardized phenotypic screen[5] to determine the effects of deletion.[6][7][8][9] Additional screens performed: - In-depth immunological phenotyping[10] | https://www.wikidoc.org/index.php/KRT31 | |
e09d3aa7c3cb0d7de090dd8caf8623500c23860a | wikidoc | KRT71 | KRT71
KRT71 is a keratin gene. Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are
subdivided into epithelial keratins and hair keratins. This gene encodes a protein that is expressed in the inner
root sheath of hair follicles. The type II keratins are clustered in a region of chromosome 12q13.(provided by
RefSeq, Jun 2009) | KRT71
KRT71 is a keratin gene. Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are
subdivided into epithelial keratins and hair keratins. This gene encodes a protein that is expressed in the inner
root sheath of hair follicles. The type II keratins are clustered in a region of chromosome 12q13.(provided by
RefSeq, Jun 2009)[full citation needed] | https://www.wikidoc.org/index.php/KRT71 | |
63c90ee03ccdc0f582dfda8a77ba4b21137f501b | wikidoc | Kampo | Kampo
Kampō (or Kanpō, 漢方) medicine is the Japanese study and adaptation of Traditional Chinese medicine. The basic works of Chinese medicine came to Japan between the 7th and 9th centuries. Since then, the Japanese have created their own unique herbal medical system and diagnosis. Kampo uses most of the Chinese medical system including acupuncture and moxibustion but is primarily concerned with the study of herbs.
# Approved Kampo medicines
Today in Japan, Kampo is integrated into the national health care system. In 1967, the Ministry of Health, Labour and Welfare approved four kampo medicines for reimbursement under the National Health Insurance (NHI) program. In 1976, 82 kampo medicines were approved by the Ministry of Health, Labour and Welfare. Currently, 148 kampo medicines are approved for reimbursement.
Rather than modifying formulae as in Traditional Chinese medicine, the Japanese kampo tradition uses fixed combinations of herbs in standardized proportions according to the classical literature of Chinese medicine. Kampo medicines are produced by various manufacturers. However, each medicine is composed of exactly the same ingredients under the Ministry's standardization methodology. The medicines are therefore prepared under strict manufacturing conditions that rival pharmaceutical companies. The two leading companies making kampo medicines are Tsumura (ツムラ) and Kanebō (カネボウ).
Extensive modern scientific research in Japan has validated the effectiveness of kampo medicines. In October 2000, a nationwide study reported that 72% of registered physicians prescribe kampo medicines.
# Herbs used in kampo medicines
The 14th edition of the Japanese Pharmacopoeia (JP) (日本薬局方 Nihon yakkyokuhō) lists 165 herbal ingredients that are used in kampo medicines.
Tsumura (ツムラ) is the leading maker of kampo medicine. They make 128 of the 148 kampo medicines. The most common herb in kampo medicine is Glycyrrhizae Radix (Chinese liquorice root). It is in 94 of the 128 Tsumura formulae. Other common herbs are Zingiberis Rhizoma (ginger) (51 of 128 formulae) and Paeoniae Radix (Chinese peony root) (44 of 128 formulae).
# Kampo outside Japan
In the United States, kampo is practiced mostly by acupuncturists, Chinese medicine practitioners, naturopath physicians, and other alternative medicine professionals. Kampo herbal formulae are studied under clinical trials, such as the clinical study of Sho-saiko-to (H09) for treatment of hepatitis C at New York Memorial Sloan-Kettering Cancer Center and liver cirrhosis caused by hepatitis C at UCSD Liver Center. Both clinical trials are sponsored by Honso USA, Inc., a branch of Honso Pharmaceutical Co., Ltd., Nagoya, Japan. | Kampo
Kampō (or Kanpō, 漢方) medicine is the Japanese study and adaptation of Traditional Chinese medicine. The basic works of Chinese medicine came to Japan between the 7th and 9th centuries. [1] Since then, the Japanese have created their own unique herbal medical system and diagnosis. Kampo uses most of the Chinese medical system including acupuncture and moxibustion but is primarily concerned with the study of herbs.
# Approved Kampo medicines
Today in Japan, Kampo is integrated into the national health care system. In 1967, the Ministry of Health, Labour and Welfare approved four kampo medicines for reimbursement under the National Health Insurance (NHI) program. In 1976, 82 kampo medicines were approved by the Ministry of Health, Labour and Welfare. Currently, 148 kampo medicines are approved for reimbursement.[2]
Rather than modifying formulae as in Traditional Chinese medicine, the Japanese kampo tradition uses fixed combinations of herbs in standardized proportions according to the classical literature of Chinese medicine. Kampo medicines are produced by various manufacturers. However, each medicine is composed of exactly the same ingredients under the Ministry's standardization methodology. The medicines are therefore prepared under strict manufacturing conditions that rival pharmaceutical companies. The two leading companies making kampo medicines are Tsumura (ツムラ) and Kanebō (カネボウ).[3]
Extensive modern scientific research in Japan has validated the effectiveness of kampo medicines. In October 2000, a nationwide study reported that 72% of registered physicians prescribe kampo medicines.[4]
# Herbs used in kampo medicines
The 14th edition of the Japanese Pharmacopoeia (JP) (日本薬局方 Nihon yakkyokuhō) lists 165 herbal ingredients that are used in kampo medicines.[5]
Tsumura (ツムラ) is the leading maker of kampo medicine.[6] They make 128 of the 148 kampo medicines. The most common herb in kampo medicine is Glycyrrhizae Radix (Chinese liquorice root). It is in 94 of the 128 Tsumura formulae. Other common herbs are Zingiberis Rhizoma (ginger) (51 of 128 formulae) and Paeoniae Radix (Chinese peony root) (44 of 128 formulae).
# Kampo outside Japan
In the United States, kampo is practiced mostly by acupuncturists, Chinese medicine practitioners, naturopath physicians, and other alternative medicine professionals. Kampo herbal formulae are studied under clinical trials, such as the clinical study of Sho-saiko-to (H09) for treatment of hepatitis C at New York Memorial Sloan-Kettering Cancer Center and liver cirrhosis caused by hepatitis C at UCSD Liver Center. Both clinical trials are sponsored by Honso USA, Inc., a branch of Honso Pharmaceutical Co., Ltd., Nagoya, Japan. | https://www.wikidoc.org/index.php/Kampo | |
5bf6467fbcff184278ac919f15b6b78d57c62fbf | wikidoc | Katal | Katal
The katal (symbol: kat) is the SI unit of catalytic activity. It is a derived SI unit for expressing quantity values of catalytic activity of enzymes and other catalysts. Its use is recommended by the General Conference on Weights and Measures and other international organizations. It replaces the non-SI enzyme unit. Enzyme units are, however, still more commonly used than the katal in practice at present, especially in biochemistry.
The katal is not used to express the rate of a reaction; that is expressed in moles per second. Rather, it is used to express catalytic activity which is a property of the catalyst. The katal is invariant of the measurement procedure, but the numerical quantity value is not and depends on the experimental conditions. Therefore, in order to define the quantity of a catalyst, the rate of conversion of a defined chemical reaction has to be specified, preferably of the first order, under strictly controlled conditions. One katal of trypsin, for example, is that amount of trypsin which breaks a mole of peptide bonds per second under specified conditions.
# Definition
kat = mol/s
# SI multiples
# Origin
The name katal has been used for decades and it became an official SI unit in 1999. | Katal
The katal (symbol: kat) is the SI unit of catalytic activity.[1] It is a derived SI unit for expressing quantity values of catalytic activity of enzymes and other catalysts. Its use is recommended by the General Conference on Weights and Measures and other international organizations. It replaces the non-SI enzyme unit. Enzyme units are, however, still more commonly used than the katal in practice at present, especially in biochemistry.
The katal is not used to express the rate of a reaction; that is expressed in moles per second. Rather, it is used to express catalytic activity which is a property of the catalyst. The katal is invariant of the measurement procedure, but the numerical quantity value is not and depends on the experimental conditions. Therefore, in order to define the quantity of a catalyst, the rate of conversion of a defined chemical reaction has to be specified, preferably of the first order, under strictly controlled conditions. One katal of trypsin, for example, is that amount of trypsin which breaks a mole of peptide bonds per second under specified conditions.
# Definition
<math> kat = mol/s </math>
# SI multiples
Template:SI multiples
# Origin
The name katal has been used for decades and it became an official SI unit in 1999. | https://www.wikidoc.org/index.php/Katal | |
20d098556c30b380fc2faa53eb6ecb8d09680ee4 | wikidoc | Kudzu | Kudzu
# Description
Kudzu is a climbing, woody or semi-woody, perennial vine capable of reaching heights of 20–30 m (66-98 ft) in trees, but also scrambles extensively over lower vegetation. The leaves are deciduous, alternate and compound, with a petiole (leaf stem) 10–20 cm (4–8 in) long and three broad leaflets 14–18 cm (6–7 in) long and 10 cm (4 in) broad. The leaflets may be entire or deeply 2–3 lobed, and are pubescent underneath with hairy margins.
The flowers are borne in long panicles 10–25 cm (about 4–10 in) long with about 30–80 individual blooms at nodes on the stems (see image).
Each flower is about 1–1.5 cm (about 0.4–0.6 in) long, purple, and highly fragrant. The flowers are copious nectar producers and are visited by many species of insects, including bees, butterflies and moths. Flowering occurs in late summer and is followed by production of brown, hairy, flattened seed pods in October and November, each of which contains three to ten hard seeds. Seeds, however, are only produced on plants that are draped over vegetation, fences, and other objects. Only one or two viable seeds are produced in a cluster of seed pods.
Once established, these plants grow rapidly, extending as much as 20 m (60 ft) per season at a rate of about 30 cm (12 in) per day. This vigorous vine may extend 10–30 m (30–100 ft) in length, with basal stems 1–10 cm (1–4 inches) in diameter. Kudzu roots are fleshy, with massive tap roots 10–20 cm (4–8 in) or more in diameter, reaching depths of up to 12 feet in older patches, and weighing as much as 180 kg. As many as thirty stems may grow from a single root crown.
Kudzu grows well under a wide range of conditions and in most soil types. Preferred habitats are forest edges, abandoned fields, roadsides, and disturbed areas, where sunlight is abundant. Kudzu grows best where winters do not drop below −15 °C (5 °F), average summer temperatures are regularly above 27 °C (80 °F), and annual rainfall is 1000 mm (40 in) or more. This fast growing plant does not do as well in less temperate areas.
# Uses
## Food
The non-woody parts of the plant are edible. The young leaves can be used for salad or cooked as a leaf vegetable; the flowers battered and fried (like squash flowers); and the starchy tuberous roots can be prepared as any root vegetable.
The starchy roots are ground into a fine powder and used for varieties of Wagashi and herbal medicines. When added to water and heated, kudzu powder becomes clear and adds stickiness to the food. It is sometimes known as "Japanese arrowroot", due to the similar culinary effect it produces.
Its leaves are high in vitamins A and C, as well as calcium and protein. Its roots are rich in starch and its flowers are an excellent honey source.
The name Kudzu appeared first in Kojiki and Nihonshoki as a type of vine or Kazura used commonly by the people who lived in Kuzu, an area around present-day Yoshino, Nara prefecture. It is unclear whether the name was taken from the people or the name of the plant was applied to the people. Kudzu has been in use for over 1300 years and it is speculated that it goes back even further. Records from the Nara and Heian era indicate that kudzu was collected and sent as a part of tax. Even today, "Yoshino Kudzu" has the best image of kudzu powder yet. The Kagoshima prefecture is the largest producer of kudzu products.
### Jelly
The purple flowers of Kudzu are also used to make a sweet jelly. This jelly is known better in the southern United States. This jelly has been described as tasting like either a cross between apple jelly and peach jelly or bubblegum. The viscous substance has a golden yellow color.
## Medicine
Studies have shown that kudzu can reduce both hangovers and alcohol cravings. A person who takes kudzu, will still drink alcohol; however, they will consume less than if they had not taken kudzu. The mechanism for this is not yet established, but it may have to do with both alcohol metabolism and the reward circuits in the brain. The Harvard Medical School is studying kudzu as a possible way to treat alcoholic cravings, by turning an extracted compound from the herb into a medical drug.
Kudzu also contains a number of useful isoflavones, including daidzein (an anti-inflammatory and antimicrobial agent), daidzin (a cancer preventive) and genistein (an antileukemic agent). Kudzu is a unique source of the isoflavone puerarin. Kudzu root compounds can affect neurotransmitters (including serotonin, GABA, and glutamate) and it has shown value in treating migraine and cluster headache.
In traditional Chinese medicine, where it is known as gé gēn (葛根), kudzu is considered one of the 50 fundamental herbs. It is used to treat tinnitus, vertigo, and Wei syndrome (superficial heat close to the surface).
## Soil improvement and preservation
Kudzu has been used as a form of erosion control and also to enhance the soil. As a legume, it increases the nitrogen in the soil via a symbiotic relationship with nitrogen-fixing bacteria in the soil. Its deep tap roots also transfer valuable minerals from the subsoil to the topsoil, thereby improving the topsoil. In the deforested section of the Central Amazon Basin in Brazil, it has been used to improve the soil pore-space in clay latosols and thus freeing even more water for plants than in the soil prior to deforestation. .
## Animal feed
Kudzu can be used by grazing animals as it is high in quality as a forage and greatly enjoyed by livestock. It can be enjoyed up until frost and even slightly after. Kudzu hay typically has a 15–18% crude protein content and over 60% total digestible nutrient value. The quality of it decreases, however, as vine content increases relative to the leaf content. Kudzu also has low forage yields despite its great deal of growth, yielding around two to four tons of dry matter per acre annually. It is also difficult to bale due to its vining growth and its slowness in shedding water. This makes it necessary to place kudzu hay under sheltered protection after being baled. Kudzu is readily consumed by all types of grazing animals, yet frequent grazing over 3 to 4 years can ruin stands. Thus kudzu only serves well as a grazing crop on a temporary basis.
## Other uses
In the Southern United States, where the plant has been introduced with devastating environmental consequences, kudzu is used to make soaps, lotions, jelly, and compost. It has even been suggested that kudzu may become a valuable asset for the production of cellulosic ethanol.
# Invasive species
Kudzu was introduced from Japan into the United States in 1876 at the Philadelphia Centennial Exposition, where it was promoted as a forage crop and an ornamental plant. From 1935 to the early 1950s the Soil Conservation Service encouraged farmers in the southeastern United States to plant kudzu to reduce soil erosion as above, and the Civilian Conservation Corps planted it widely for many years.
However, it would soon be discovered that the southeastern US has near-perfect conditions for kudzu to grow out of control — hot, humid summers, frequent rainfall, temperate winters with few hard freezes (kudzu cannot tolerate low freezing temperatures that bring the frost line down through its entire root system, a rare occurrence in this region), and no natural predators. As such, the once-promoted plant was named a pest weed by the United States Department of Agriculture in 1953.
Kudzu is now common throughout most of the southeastern United States, and has been found as far north as Paterson, New Jersey, and as far south as Key West, Florida. It has also been found growing (rather inexplicably) in Clackamas County, Oregon in 2000. Kudzu has naturalized into about 20,000 to 30,000 square kilometers of land in the United States and costs around $500 million annually in lost cropland and control costs.
Kudzu is also becoming a problem in northeastern Australia and has been seen in yet isolated spots in northern Italy (Lago Maggiore).
The spread of kudzu is mainly by vegetative expansion by stolons (runners) that root at the nodes to form new plants and by rhizomes. Kudzu will also spread by seeds, which are contained in pods and mature in the autumn, although this is rarer. One or two viable seeds are produced per cluster of pods. These hard-coated seeds may not germinate for several years, which can result in the re-appearance of the species years after it was thought eradicated at a site.
## Control
For successful long-term control of kudzu, it is not necessary to destroy the entire root system, which can be quite large and deep. It is only necessary to use some method to kill or remove the kudzu root crown and all rooting runners. The root crown is a fibrous knob of tissue that sits on top of the root (rhizome). Crowns form from vine nodes that root to the ground, and range from pea-size to basketball-size. The older the crown, the deeper they tend to be found in the ground because they are covered by sediment and plant debris over time. Nodes and crowns are the source of all kudzu vines, and roots cannot produce vines. If any portion of a root crown remains after attempted removal, the kudzu plant grows back.
Mechanical methods of control involve cutting off crowns from roots, usually just below ground level. This immediately kills the plant. Cutting off vines is not sufficient for an immediate kill. It is necessary to destroy all removed crown material: Buried crowns can regenerate into healthy kudzu. Transporting crowns in soil removed from a kudzu infestation is one common way that kudzu "miraculously" spreads and shows up in unexpected locations.
Close mowing every week, regular heavy grazing for many successive years, or repeated cultivation may be effective, if this serves to deplete root reserves. If done in the spring, cutting off vines must be repeated as regrowth appears to exhaust the plant's stored carbohydrate reserves. Cut kudzu can be fed to livestock, burned, or composted.
Late-season cutting should be followed up with immediate application of a systemic herbicide to the cut stems, to encourage transport of the herbicide into the root system. Repeated applications of several soil-active herbicides have been used effectively on large infestations in forestry situations.
Prescribed burning is also used on old extensive infestations in order to remove vegetative cover and promote seed germination for removal or treatment. It is usually done to prepare for treatment of the root crowns. Landscape equipment, such as a skid loader ("Bobcat"), can also remove biomass. While fire is not an effective way to kill kudzu, equipment such as skid loaders can remove crowns and thereby kill kudzu with minimal disturbance of soil.
Efforts are currently being organized by the U.S. Forest Service to search for biological control agents for kudzu. Several fungi are pathogenic to kudzu. Colletotrichum gloeosporioides is one tested example.
The city of Chattanooga, Tennessee has undertaken a trial program using goats and llamas that graze on the plant. The llamas serve double-duty as defense against predators due to their aggressive nature. Currently the goats are grazing along the Missionary Ridge area in the east of the city. | Kudzu
Template:Nihongo, Pueraria lobata (syn. P. montana, P. thunbergiana), is one of about 20 species in the genus Pueraria in the pea family Fabaceae, subfamily Faboideae. It is native to southern Japan and southeast China in eastern Asia. The name comes from the Japanese word for this plant, kuzu. The other species of Pueraria occur in southeast Asia, further south.
# Description
Kudzu is a climbing, woody or semi-woody, perennial vine capable of reaching heights of 20–30 m (66-98 ft) in trees, but also scrambles extensively over lower vegetation. The leaves are deciduous, alternate and compound, with a petiole (leaf stem) 10–20 cm (4–8 in) long and three broad leaflets 14–18 cm (6–7 in) long and 10 cm (4 in) broad. The leaflets may be entire or deeply 2–3 lobed, and are pubescent underneath with hairy margins.
The flowers are borne in long panicles 10–25 cm (about 4–10 in) long with about 30–80 individual blooms at nodes on the stems (see image).
Each flower is about 1–1.5 cm (about 0.4–0.6 in) long, purple, and highly fragrant. The flowers are copious nectar producers and are visited by many species of insects, including bees, butterflies and moths. Flowering occurs in late summer and is followed by production of brown, hairy, flattened seed pods in October and November, each of which contains three to ten hard seeds. Seeds, however, are only produced on plants that are draped over vegetation, fences, and other objects. Only one or two viable seeds are produced in a cluster of seed pods.[1]
Once established, these plants grow rapidly, extending as much as 20 m (60 ft) per season at a rate of about 30 cm (12 in) per day. This vigorous vine may extend 10–30 m (30–100 ft) in length, with basal stems 1–10 cm (1–4 inches) in diameter. Kudzu roots are fleshy, with massive tap roots 10–20 cm (4–8 in) or more in diameter, reaching depths of up to 12 feet in older patches, and weighing as much as 180 kg. As many as thirty stems may grow from a single root crown.
Kudzu grows well under a wide range of conditions and in most soil types. Preferred habitats are forest edges, abandoned fields, roadsides, and disturbed areas, where sunlight is abundant. Kudzu grows best where winters do not drop below −15 °C (5 °F), average summer temperatures are regularly above 27 °C (80 °F), and annual rainfall is 1000 mm (40 in) or more. This fast growing plant does not do as well in less temperate areas.
# Uses
## Food
The non-woody parts of the plant are edible. The young leaves can be used for salad or cooked as a leaf vegetable; the flowers battered and fried (like squash flowers); and the starchy tuberous roots can be prepared as any root vegetable.
The starchy roots are ground into a fine powder and used for varieties of Wagashi and herbal medicines. When added to water and heated, kudzu powder becomes clear and adds stickiness to the food. It is sometimes known as "Japanese arrowroot", due to the similar culinary effect it produces.[2]
Its leaves are high in vitamins A and C, as well as calcium and protein. Its roots are rich in starch and its flowers are an excellent honey source.[3]
The name Kudzu appeared first in Kojiki and Nihonshoki as a type of vine or Kazura used commonly by the people who lived in Kuzu, an area around present-day Yoshino, Nara prefecture. It is unclear whether the name was taken from the people or the name of the plant was applied to the people. Kudzu has been in use for over 1300 years and it is speculated that it goes back even further. Records from the Nara and Heian era indicate that kudzu was collected and sent as a part of tax. Even today, "Yoshino Kudzu" has the best image of kudzu powder yet. The Kagoshima prefecture is the largest producer of kudzu products.[citation needed]
### Jelly
The purple flowers of Kudzu are also used to make a sweet jelly. This jelly is known better in the southern United States. This jelly has been described as tasting like either a cross between apple jelly and peach jelly or bubblegum.[citation needed] The viscous substance has a golden yellow color.
## Medicine
Studies have shown that kudzu can reduce both hangovers and alcohol cravings.[4][5][6] A person who takes kudzu, will still drink alcohol; however, they will consume less than if they had not taken kudzu.[7] The mechanism for this is not yet established, but it may have to do with both alcohol metabolism and the reward circuits in the brain. The Harvard Medical School is studying kudzu as a possible way to treat alcoholic cravings, by turning an extracted compound from the herb into a medical drug.[8]
Kudzu also contains a number of useful isoflavones, including daidzein (an anti-inflammatory and antimicrobial agent), daidzin (a cancer preventive) and genistein (an antileukemic agent). Kudzu is a unique source of the isoflavone puerarin. Kudzu root compounds can affect neurotransmitters (including serotonin, GABA, and glutamate) and it has shown value in treating migraine and cluster headache.[9]
In traditional Chinese medicine, where it is known as gé gēn (葛根), kudzu is considered one of the 50 fundamental herbs. It is used to treat tinnitus, vertigo, and Wei syndrome (superficial heat close to the surface).[citation needed]
## Soil improvement and preservation
Kudzu has been used as a form of erosion control and also to enhance the soil. As a legume, it increases the nitrogen in the soil via a symbiotic relationship with nitrogen-fixing bacteria in the soil.[3] Its deep tap roots also transfer valuable minerals from the subsoil to the topsoil, thereby improving the topsoil. In the deforested section of the Central Amazon Basin in Brazil, it has been used to improve the soil pore-space in clay latosols and thus freeing even more water for plants than in the soil prior to deforestation.[10] .
## Animal feed
Kudzu can be used by grazing animals as it is high in quality as a forage and greatly enjoyed by livestock. It can be enjoyed up until frost and even slightly after. Kudzu hay typically has a 15–18% crude protein content and over 60% total digestible nutrient value. The quality of it decreases, however, as vine content increases relative to the leaf content. Kudzu also has low forage yields despite its great deal of growth, yielding around two to four tons of dry matter per acre annually. It is also difficult to bale due to its vining growth and its slowness in shedding water. This makes it necessary to place kudzu hay under sheltered protection after being baled. Kudzu is readily consumed by all types of grazing animals, yet frequent grazing over 3 to 4 years can ruin stands. Thus kudzu only serves well as a grazing crop on a temporary basis.[1]
## Other uses
In the Southern United States, where the plant has been introduced with devastating environmental consequences,[11] kudzu is used to make soaps, lotions, jelly, and compost.[12][13] It has even been suggested that kudzu may become a valuable asset for the production of cellulosic ethanol.[14]
# Invasive species
Kudzu was introduced from Japan into the United States in 1876 at the Philadelphia Centennial Exposition, where it was promoted as a forage crop and an ornamental plant. From 1935 to the early 1950s the Soil Conservation Service encouraged farmers in the southeastern United States to plant kudzu to reduce soil erosion as above, and the Civilian Conservation Corps planted it widely for many years.
However, it would soon be discovered that the southeastern US has near-perfect conditions for kudzu to grow out of control — hot, humid summers, frequent rainfall, temperate winters with few hard freezes (kudzu cannot tolerate low freezing temperatures that bring the frost line down through its entire root system, a rare occurrence in this region), and no natural predators. As such, the once-promoted plant was named a pest weed by the United States Department of Agriculture in 1953.
Kudzu is now common throughout most of the southeastern United States, and has been found as far north as Paterson, New Jersey, and as far south as Key West, Florida.[citation needed] It has also been found growing (rather inexplicably) in Clackamas County, Oregon in 2000.[15] Kudzu has naturalized into about 20,000 to 30,000 square kilometers of land in the United States and costs around $500 million annually in lost cropland and control costs.
Kudzu is also becoming a problem in northeastern Australia and has been seen in yet isolated spots in northern Italy (Lago Maggiore).
The spread of kudzu is mainly by vegetative expansion by stolons (runners) that root at the nodes to form new plants and by rhizomes. Kudzu will also spread by seeds, which are contained in pods and mature in the autumn, although this is rarer. One or two viable seeds are produced per cluster of pods. These hard-coated seeds may not germinate for several years, which can result in the re-appearance of the species years after it was thought eradicated at a site.[citation needed]
## Control
For successful long-term control of kudzu, it is not necessary to destroy the entire root system, which can be quite large and deep. It is only necessary to use some method to kill or remove the kudzu root crown[16] and all rooting runners. The root crown is a fibrous knob of tissue that sits on top of the root (rhizome). Crowns form from vine nodes that root to the ground, and range from pea-size to basketball-size.[16] The older the crown, the deeper they tend to be found in the ground because they are covered by sediment and plant debris over time. Nodes and crowns are the source of all kudzu vines, and roots cannot produce vines. If any portion of a root crown remains after attempted removal, the kudzu plant grows back.
Mechanical methods of control involve cutting off crowns from roots, usually just below ground level. This immediately kills the plant. Cutting off vines is not sufficient for an immediate kill. It is necessary to destroy all removed crown material: Buried crowns can regenerate into healthy kudzu. Transporting crowns in soil removed from a kudzu infestation is one common way that kudzu "miraculously" spreads and shows up in unexpected locations.
Close mowing every week, regular heavy grazing for many successive years, or repeated cultivation may be effective, if this serves to deplete root reserves.[16] If done in the spring, cutting off vines must be repeated as regrowth appears to exhaust the plant's stored carbohydrate reserves. Cut kudzu can be fed to livestock, burned, or composted.
Late-season cutting should be followed up with immediate application of a systemic herbicide to the cut stems, to encourage transport of the herbicide into the root system. Repeated applications of several soil-active herbicides have been used effectively on large infestations in forestry situations.[16]
Prescribed burning is also used on old extensive infestations in order to remove vegetative cover and promote seed germination for removal or treatment. It is usually done to prepare for treatment of the root crowns.[17] Landscape equipment, such as a skid loader ("Bobcat"), can also remove biomass. While fire is not an effective way to kill kudzu,[16] equipment such as skid loaders can remove crowns and thereby kill kudzu with minimal disturbance of soil.[16]
Efforts are currently being organized by the U.S. Forest Service to search for biological control agents for kudzu. Several fungi are pathogenic to kudzu. Colletotrichum gloeosporioides is one tested example.
The city of Chattanooga, Tennessee has undertaken a trial program using goats and llamas that graze on the plant. The llamas serve double-duty as defense against predators due to their aggressive nature. Currently the goats are grazing along the Missionary Ridge area in the east of the city.[18] | https://www.wikidoc.org/index.php/Kudzu | |
a3f03db818f8a44100aa8304844a510260037c96 | wikidoc | Kumis | Kumis
Kumis is a fermented dairy product traditionally made from mares' milk. The drink remains important to the people of the Central Asian steppes, including the Bashkirs, Kazakhs, Kyrgyz, Mongols and Yakuts.
Kumis is a dairy product similar to kefir, but is produced from a liquid starter culture, in contrast to the solid kefir "grains". Because mare's milk contains more sugars than the cow's or goat's milk fermented into kefir, kumis has a higher, though still mild, alcohol content. Even in the areas of the world where kumis is popular today, mare's milk remains a very limited commodity. Industrial-scale production of kumis therefore generally uses cow's milk, which is richer in fat and protein but lower in lactose than the milk from a horse. Before fermentation, the cow's milk is fortified in one of several ways. Sucrose, a simple sugar, may be added, to allow a comparable fermentation. Another technique adds modified whey in order to better approximate the composition of mare's milk.
# Terminology and etymology
Kumis is also transliterated kumiss, koumiss, kymys or kymyz. It comes from the Turkic word kımız. The word kumis is thought to derive from the name of the Turkic Kumyk people.
The drink is also called airag, ayrag or chigee in Mongolian.
# Production of mare's milk
A 1982 source reported that 230,000 horses were kept in Russia specifically for producing milk to make into kumis.
Rinchingiin Indra, writing about Mongolian dairying, says "it takes considerable skill to milk a mare" and describes the technique: the milker kneels on one knee, with a pail propped on the other, steadied by a string tied to an arm. One arm is wrapped behind the mare's rear leg and the other in front. A foal starts the milk flow and is pulled away by another person, but left touching the mare's side during the entire process.
In Mongolia, the milking season for horses traditionally runs between mid-June and early October. During one season, a mare produces approximately 1,000 to 1,200 kilograms of milk, of which about half is left to the foals.
# Nutritional properties of mare's milk
According to one modern source, "unfermented mare's milk is generally not drunk", because it is a strong laxative. Varro's On Agriculture, from the 1st century BC, also mentions this: "as a laxative the best is mare's milk, then donkey's milk, cow's milk, and finally goat's milk..." Yet today mare's milk is sometimes recommended as a substitute for cow's milk for people with milk allergies, and little mention is made of this laxative effect.
In fact, mare's milk is well-tolerated by people of northern European descent and others who are lactose tolerant. They can digest lactose even as adults; most of the world's population cannot, including the majority in the Central Asian steppes where kumis is popular. Mare's milk has almost 40% more lactose than cow's milk (and, validating Varro's observations, goat's milk has even less); drinking six ounces (190 ml) a day would be enough to give a lactose-intolerant person severe intestinal symptoms. During fermentation, the lactose is converted into lactic acid, ethanol, and carbon dioxide, and the milk becomes an accessible source of nutrition.
# Production of kumis
Kumis is made by fermenting mare's milk over the course of hours or days, often while stirring or churning. During the fermentation, Lactobacilli bacteria acidify the milk, and yeasts turn it into a carbonated and mildly alcoholic drink.
Traditionally, this fermentation took place in a horse-hide container, which might be left on the top of the yurt and turned over on occasion, or strapped to the saddle and joggled around over the course of a day's riding. Today, a wooden vat or plastic barrel may be used in place of the leather container.
In modern controlled production, the initial fermentation takes two to five hours at a temperature of around 27°C (80°F); this may be followed by a cooler aging period. The finished product contains between 0.7 and 2.5% alcohol.
Kumis itself has a very low level of alcohol, comparable to small beer, the common drink of medieval Europe that also avoided the consumption of potentially contaminated water. Kumis can, however, be strengthened through freeze distillation, a technique Central Asian nomads are reported to have employed. It can also be distilled into the spirit known as araka or arkhi.
# History
Kumis is an ancient beverage. Herodotus, in his 5th century BC Histories, describes the Scythians' processing of mare's milk:
The milk thus obtained is poured into deep wooden casks, about which the blind slaves are placed, and then the milk is stirred round. That which rises to the top is drawn off, and considered the best part; the under portion is of less account.
It is widely believed that this is a description of ancient kumis making, and it matches up well enough with later accounts, such as this one given by 13th-century traveller William of Rubruck:
This cosmos, which is mare's milk, is made in this wise. When they have got together a great quantity of milk, which is as sweet as cow's as long as it is fresh, they pour it into a big skin or bottle, and they set to churning it with a stick and when they have beaten it sharply it begins to boil up like new wine and to sour or ferment, and they continue to churn it until they have extracted the butter. Then they taste it, and when it is mildly pungent, they drink it. It is pungent on the tongue like rapé wine when drunk, and when a man has finished drinking, it leaves a taste of milk of almonds on the tongue, and it makes the inner man most joyful and also intoxicates weak heads, and greatly provokes urine.
# Health
Toward the end of the 19th century, kumis had a strong enough reputation as a cure-all to support a small industry of "kumis cure" resorts, mostly in southeastern Russia, where patients were "furnished with suitable light and varied amusement" during their treatment, which consisted of drinking large quantities of kumis. W. Gilman Thompson's 1906 Practical Diatetics reports that kumis has been cited as beneficial for a range of chronic diseases, including tuberculosis, bronchitis, catarrh, and anemia. Gilman also says that a large part of the credit for the successes of the "kumis cure" is due not to the beverage, but to favorable summer climates at the resorts. Among notables to try the kumis cure were writers Leo Tolstoy and Anton Chekhov. Chekhov, long-suffering from tuberculosis, checked into a kumis cure resort in 1901. Drinking four bottles a day for two weeks, he gained 12 pounds but no cure.
# Consumption
Strictly speaking, kumis is in its own category of alcoholic drinks because it is made neither from fruit nor from grain. Technically, it is closer by definition to wine than to beer because the fermentation occurs directly from sugars, as in wine (usually from fruit), as opposed to from starches (usually from grain) that had been first worted to be converted to sugars, as in beer. But in terms of experience and traditional manner of consumption it is much more comparable to beer. It is even milder in alcoholic content than beer and is usually consumed cold. It is arguably the region’s beer equivalent.
Kumis is very light in body compared to most dairy drinks. It has a unique, slightly sour flavor with a bite from the mild alcoholic content. The exact flavor is greatly variable between different brewers.
As indicated above, kumis is usually served cold or chilled. Traditionally it is sipped out of small, handle-less, bowl-shaped cups or saucers, called pialkas. The serving of it is an essential part of Kyrgyz hospitality on the jailoo or high pasture, where they keep their herds of animals (horse, cattle, and sheep) during the summer phase of transhumance.
One custom that may be disturbing to the visitor's notions of hygiene is that of pouring the dregs of each cup back into the kumis storage container. That way, none is wasted, and the hostess assures herself that there will be enough for future visitors.
# Its cultural role
The capital of Kyrgyzstan, Bishkek, is named after the paddle used to churn the fermenting milk, showing the importance of the drink in the national culture.
In 2005, George W. Bush visited Mongolia, becoming the first U.S. president to do so, "and probably the first to drink fermented mare's milk in a felt tent guarded by the latter-day Golden Horde and a herd of camels and yaks", according to the Washington Post. The same article casts doubt on whether Bush actually drank: "No word on whether Bush actually swallowed or not, but some of his aides evidently did, judging by the looks on their faces afterward." | Kumis
Kumis is a fermented dairy product traditionally made from mares' milk. The drink remains important to the people of the Central Asian steppes, including the Bashkirs, Kazakhs, Kyrgyz, Mongols and Yakuts.[1]
Kumis is a dairy product similar to kefir, but is produced from a liquid starter culture, in contrast to the solid kefir "grains". Because mare's milk contains more sugars than the cow's or goat's milk fermented into kefir, kumis has a higher, though still mild, alcohol content. Even in the areas of the world where kumis is popular today, mare's milk remains a very limited commodity. Industrial-scale production of kumis therefore generally uses cow's milk, which is richer in fat and protein but lower in lactose than the milk from a horse. Before fermentation, the cow's milk is fortified in one of several ways. Sucrose, a simple sugar, may be added, to allow a comparable fermentation. Another technique adds modified whey in order to better approximate the composition of mare's milk.[2]
# Terminology and etymology
Kumis is also transliterated kumiss, koumiss, kymys or kymyz. It comes from the Turkic word kımız.[3] The word kumis is thought to derive from the name of the Turkic Kumyk people.[4]
The drink is also called airag, ayrag or chigee in Mongolian. [5]
# Production of mare's milk
A 1982 source reported that 230,000 horses were kept in Russia specifically for producing milk to make into kumis.[6]
Rinchingiin Indra, writing about Mongolian dairying, says "it takes considerable skill to milk a mare" and describes the technique: the milker kneels on one knee, with a pail propped on the other, steadied by a string tied to an arm. One arm is wrapped behind the mare's rear leg and the other in front. A foal starts the milk flow and is pulled away by another person, but left touching the mare's side during the entire process.[7]
In Mongolia, the milking season for horses traditionally runs between mid-June and early October. During one season, a mare produces approximately 1,000 to 1,200 kilograms of milk, of which about half is left to the foals.[8]
# Nutritional properties of mare's milk
According to one modern source, "unfermented mare's milk is generally not drunk", because it is a strong laxative.[1] Varro's On Agriculture, from the 1st century BC, also mentions this: "as a laxative the best is mare's milk, then donkey's milk, cow's milk, and finally goat's milk..."[9] Yet today mare's milk is sometimes recommended as a substitute for cow's milk for people with milk allergies, and little mention is made of this laxative effect.
In fact, mare's milk is well-tolerated by people of northern European descent and others who are lactose tolerant. They can digest lactose even as adults; most of the world's population cannot, including the majority in the Central Asian steppes where kumis is popular. Mare's milk has almost 40% more lactose than cow's milk[10] (and, validating Varro's observations, goat's milk has even less); drinking six ounces (190 ml) a day would be enough to give a lactose-intolerant person severe intestinal symptoms. During fermentation, the lactose is converted into lactic acid, ethanol, and carbon dioxide, and the milk becomes an accessible source of nutrition.[11]
# Production of kumis
Kumis is made by fermenting mare's milk over the course of hours or days, often while stirring or churning. During the fermentation, Lactobacilli bacteria acidify the milk, and yeasts turn it into a carbonated and mildly alcoholic drink.
Traditionally, this fermentation took place in a horse-hide container, which might be left on the top of the yurt and turned over on occasion, or strapped to the saddle and joggled around over the course of a day's riding. Today, a wooden vat or plastic barrel may be used in place of the leather container.[12]
In modern controlled production, the initial fermentation takes two to five hours at a temperature of around 27°C (80°F); this may be followed by a cooler aging period.[13] The finished product contains between 0.7 and 2.5% alcohol.[14]
Kumis itself has a very low level of alcohol, comparable to small beer, the common drink of medieval Europe that also avoided the consumption of potentially contaminated water. Kumis can, however, be strengthened through freeze distillation, a technique Central Asian nomads are reported to have employed.[15] It can also be distilled into the spirit known as araka or arkhi. [16]
# History
Kumis is an ancient beverage. Herodotus, in his 5th century BC Histories, describes the Scythians' processing of mare's milk:
The milk thus obtained is poured into deep wooden casks, about which the blind slaves are placed, and then the milk is stirred round. That which rises to the top is drawn off, and considered the best part; the under portion is of less account.[17]
It is widely believed that this is a description of ancient kumis making,[4] and it matches up well enough with later accounts, such as this one given by 13th-century traveller William of Rubruck:
This cosmos, which is mare's milk, is made in this wise. [...] When they have got together a great quantity of milk, which is as sweet as cow's as long as it is fresh, they pour it into a big skin or bottle, and they set to churning it with a stick [...] and when they have beaten it sharply it begins to boil up like new wine and to sour or ferment, and they continue to churn it until they have extracted the butter. Then they taste it, and when it is mildly pungent, they drink it. It is pungent on the tongue like rapé wine when drunk, and when a man has finished drinking, it leaves a taste of milk of almonds on the tongue, and it makes the inner man most joyful and also intoxicates weak heads, and greatly provokes urine.[18]
# Health
Toward the end of the 19th century, kumis had a strong enough reputation as a cure-all to support a small industry of "kumis cure" resorts, mostly in southeastern Russia, where patients were "furnished with suitable light and varied amusement" during their treatment, which consisted of drinking large quantities of kumis.[19] W. Gilman Thompson's 1906 Practical Diatetics reports that kumis has been cited as beneficial for a range of chronic diseases, including tuberculosis, bronchitis, catarrh, and anemia. Gilman also says that a large part of the credit for the successes of the "kumis cure" is due not to the beverage, but to favorable summer climates at the resorts.[20] Among notables to try the kumis cure were writers Leo Tolstoy and Anton Chekhov. Chekhov, long-suffering from tuberculosis, checked into a kumis cure resort in 1901. Drinking four bottles a day for two weeks, he gained 12 pounds but no cure.[21]
# Consumption
Strictly speaking, kumis is in its own category of alcoholic drinks because it is made neither from fruit nor from grain. Technically, it is closer by definition to wine than to beer because the fermentation occurs directly from sugars, as in wine (usually from fruit), as opposed to from starches (usually from grain) that had been first worted to be converted to sugars, as in beer. But in terms of experience and traditional manner of consumption it is much more comparable to beer. It is even milder in alcoholic content than beer and is usually consumed cold. It is arguably the region’s beer equivalent.
Kumis is very light in body compared to most dairy drinks. It has a unique, slightly sour flavor with a bite from the mild alcoholic content. The exact flavor is greatly variable between different brewers.
As indicated above, kumis is usually served cold or chilled. Traditionally it is sipped out of small, handle-less, bowl-shaped cups or saucers, called pialkas. The serving of it is an essential part of Kyrgyz hospitality on the jailoo or high pasture, where they keep their herds of animals (horse, cattle, and sheep) during the summer phase of transhumance.
One custom that may be disturbing to the visitor's notions of hygiene is that of pouring the dregs of each cup back into the kumis storage container. That way, none is wasted, and the hostess assures herself that there will be enough for future visitors.
# Its cultural role
The capital of Kyrgyzstan, Bishkek, is named after the paddle used to churn the fermenting milk, showing the importance of the drink in the national culture.
In 2005, George W. Bush visited Mongolia, becoming the first U.S. president to do so, "and probably the first to drink fermented mare's milk in a felt tent guarded by the latter-day Golden Horde and a herd of camels and yaks", according to the Washington Post.[22] The same article casts doubt on whether Bush actually drank: "No word on whether Bush actually swallowed or not, but some of his aides evidently did, judging by the looks on their faces afterward."[22] | https://www.wikidoc.org/index.php/Kumis | |
5ef225fa6d216d28efaaed2f8b8712df18178d6e | wikidoc | Kv1.1 | Kv1.1
Potassium voltage-gated channel subfamily A member 1 also known as Kv1.1 is a shaker related voltage-gated potassium channel that in humans is encoded by the KCNA1 gene. The Isaacs syndrome is a result of an autoimmune reaction against the Kv1.1 ion channel.
# Genomics
The gene is located on the Watson (plus) strand of the short arm of chromosome 12 (12p13.32). The gene itself is 8,348 bases in length and encodes a protein of 495 amino acids (predicted molecular weight 56.466 kiloDaltons).
# Alternative names
The recommended name for this protein is potassium voltage-gated channel subfamily A member 1 but a number of alternatives have been used in the literature including HuK1 (human K+ channel I), RBK1 (rubidium potassium channel 1), MBK (mouse brain K+ channel), voltage gated potassium channel HBK1, voltage gated potassium channel subunit Kv1.1, voltage-gated K+ channel HuKI and AEMK (associated with myokymia with periodic ataxia).
# Structure
The protein is believed to have six domains (S1-S6) with the loop between S5 and S6 forming the channel pore. This region also has a conserved selectivity filter motif. The functional channel is a homotetramer. The N-terminus of the protein associates with β subunits. These subunits regulate channel inactivation as well as its expression. The C-terminus is associated with a PDZ domain protein involved in channel targeting.
# Function
The protein functions as a potassium selective channel through which the potassium ion may pass in consensus with the electrochemical gradient. They play a role in repolarisation of membranes.
# RNA editing
The pre-mRNA of this protein is subject to RNA editing.
## Type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs (e.g. Potassium channel RNA editing signal) and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double stranded regions of RNA are formed by base-pairing between residues in the region close to the editing site with residues usually in a neighboring intron but can sometimes be an exonic sequence too. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).
## Location
The modified residue is found at amino acid 400 of the final protein. This is located in the sixth transmembrane region found, which corresponds to the inner vestibule of the pore. A stem loop hairpin structure mediates the RNA editing. ADAR2 is likely to be the preferred editing enzyme at the I/V site. Editing results in a codon alteration from ATT to GTT, resulting in an amino acid change from isoleucine to valine. ADAR2 enzyme is the major editing enzyme. The MFOLD programme predicted that the minimum region required for editing would form an imperfect inverted repeat hairpin. This region is composed of a 114 base pairs. Similar regions have been identified in mouse and rat. The edited adenosine is found in a 6-base pair duplex region. Mutation experiment in the region near the 6-base pair duplex have shown that the specific bases in this region were also essential for editing to occur. The region required for editing is unusual in that the hairpin structure is formed by exonic sequences only. In the majority of A to I editing the ECS is found within an intronic sequence.
## Conservation
The editing is highly conserved having been observed in squid, fruit fly, mouse, and rat.
## Regulation
Editing levels vary in different tissues: 17% in the caudate nucleus, 68% in the spinal cord, and 77% in the medulla.
## Consequences
### Structure
Editing results in a codon (I/V) change from (ATT) to (GTT) resulting in translation of a valine instead of an isoleucine at the position of the editing site. Valine has a larger side-chain. RNA editing at this position occurs at a highly conserved ion conducting pore of the channel. This may affect the channels role in the process of fast inactivation.
### Function
Voltage-dependent potassium channels modulate excitability by opening and closing a potassium selective pore in response to voltage. The flow of potassium ions is interrupted by interaction of an inactivating particle, an auxiliary protein in humans but an intrinsic part of the channel in other species. The I to V amino acid change is thought to disrupt the hydrophobic interaction between the inactivating particle and the pore lining. This interrupts the process of fast inactivation. Activation kinetics are unaffected by RNA editing. Changes in inactivation kinetics affect the duration and frequency of the action potential. An edited channel passes more current and has a shorter action potential than the non-edited type due to the inability of the inactivating particle to interact with the residue in the ion-conducting pore of the channel.This was determined by electrophysiology analysis. The length of time the membrane is depolarised is decreased, which also reduces the efficiency of transmitter release. Since editing can cause amino acid changes in 1- 4 in potassium channel tetramers, it can have a wide variety of effects on channel inactivation.
## Dysregulation
Changes in the process of fast inactivation are known to have behavioral and neurological consequences in vivo.
# Clinical
Mutations in this gene cause episodic ataxia type 1. | Kv1.1
Potassium voltage-gated channel subfamily A member 1 also known as Kv1.1 is a shaker related voltage-gated potassium channel that in humans is encoded by the KCNA1 gene.[1][2][3] The Isaacs syndrome is a result of an autoimmune reaction against the Kv1.1 ion channel.[4]
# Genomics
The gene is located on the Watson (plus) strand of the short arm of chromosome 12 (12p13.32). The gene itself is 8,348 bases in length and encodes a protein of 495 amino acids (predicted molecular weight 56.466 kiloDaltons).
# Alternative names
The recommended name for this protein is potassium voltage-gated channel subfamily A member 1 but a number of alternatives have been used in the literature including HuK1 (human K+ channel I), RBK1 (rubidium potassium channel 1), MBK (mouse brain K+ channel), voltage gated potassium channel HBK1, voltage gated potassium channel subunit Kv1.1, voltage-gated K+ channel HuKI and AEMK (associated with myokymia with periodic ataxia).
# Structure
The protein is believed to have six domains (S1-S6) with the loop between S5 and S6 forming the channel pore. This region also has a conserved selectivity filter motif. The functional channel is a homotetramer. The N-terminus of the protein associates with β subunits. These subunits regulate channel inactivation as well as its expression. The C-terminus is associated with a PDZ domain protein involved in channel targeting.[5][6]
# Function
The protein functions as a potassium selective channel through which the potassium ion may pass in consensus with the electrochemical gradient. They play a role in repolarisation of membranes.[5]
# RNA editing
The pre-mRNA of this protein is subject to RNA editing.[7]
## Type
A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs (e.g. Potassium channel RNA editing signal) and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 is restricted to the brain. The double stranded regions of RNA are formed by base-pairing between residues in the region close to the editing site with residues usually in a neighboring intron but can sometimes be an exonic sequence too. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).
## Location
The modified residue is found at amino acid 400 of the final protein. This is located in the sixth transmembrane region found, which corresponds to the inner vestibule of the pore. A stem loop hairpin structure mediates the RNA editing. ADAR2 is likely to be the preferred editing enzyme at the I/V site. Editing results in a codon alteration from ATT to GTT, resulting in an amino acid change from isoleucine to valine. ADAR2 enzyme is the major editing enzyme. The MFOLD programme predicted that the minimum region required for editing would form an imperfect inverted repeat hairpin. This region is composed of a 114 base pairs. Similar regions have been identified in mouse and rat. The edited adenosine is found in a 6-base pair duplex region. Mutation experiment in the region near the 6-base pair duplex have shown that the specific bases in this region were also essential for editing to occur. The region required for editing is unusual in that the hairpin structure is formed by exonic sequences only. In the majority of A to I editing the ECS is found within an intronic sequence.[7]
## Conservation
The editing is highly conserved having been observed in squid, fruit fly, mouse, and rat.[7]
## Regulation
Editing levels vary in different tissues: 17% in the caudate nucleus, 68% in the spinal cord, and 77% in the medulla.[8]
## Consequences
### Structure
Editing results in a codon (I/V) change from (ATT) to (GTT) resulting in translation of a valine instead of an isoleucine at the position of the editing site. Valine has a larger side-chain. RNA editing at this position occurs at a highly conserved ion conducting pore of the channel. This may affect the channels role in the process of fast inactivation.[9]
### Function
Voltage-dependent potassium channels modulate excitability by opening and closing a potassium selective pore in response to voltage. The flow of potassium ions is interrupted by interaction of an inactivating particle, an auxiliary protein in humans but an intrinsic part of the channel in other species. The I to V amino acid change is thought to disrupt the hydrophobic interaction between the inactivating particle and the pore lining. This interrupts the process of fast inactivation. Activation kinetics are unaffected by RNA editing.[7] Changes in inactivation kinetics affect the duration and frequency of the action potential. An edited channel passes more current and has a shorter action potential than the non-edited type due to the inability of the inactivating particle to interact with the residue in the ion-conducting pore of the channel.This was determined by electrophysiology analysis.[10] The length of time the membrane is depolarised is decreased, which also reduces the efficiency of transmitter release.[8] Since editing can cause amino acid changes in 1- 4 in potassium channel tetramers, it can have a wide variety of effects on channel inactivation.
## Dysregulation
Changes in the process of fast inactivation are known to have behavioral and neurological consequences in vivo.[7]
# Clinical
Mutations in this gene cause episodic ataxia type 1. | https://www.wikidoc.org/index.php/Kv1.1 | |
9debecf4954269b75c1f9017169e4f16f6d0ad74 | wikidoc | Kvass | Kvass
Kvass (literally "leaven"; borrowed in the 16th century from Russian квас), sometimes translated into English as bread drink, is a fermented mildly alcoholic beverage made from black or rye bread. It is popular in Russia, Belarus, Ukraine and other Eastern and Central European countries as well as in all ex-Soviet states, like Uzbekistan, where one can see many kvass vendors in the streets.
The alcohol content is so low (0.05-1.44%) that it is considered acceptable for consumption by children. It is often flavoured with fruits or herbs such as strawberries or mint. Russians also use kvass for cooking a special summer cold soup, okroshka.
# History
Kvass has been a common drink in Eastern Europe since ancient times. It was at first mentioned in old-russian chronicles under 989. It has been both a commercial product and homemade. It used to be consumed widely in most Slavic countries, and in almost every city there are kvass vendors on the street.
# Manufacturing
Kvass is made by the natural fermentation of bread made from wheat, rye, or barley, and sometimes flavoured with fruit, berries, raisins or birch sap collected in the early spring.
Modern homemade kvass most often uses black or rye bread, usually dried, baked into croutons (called suharki), or fried, with the addition of sugar or fruit (e.g. apples or raisins), and with a yeast culture and zakvasska ("kvass fermentation starter").
Commercial kvass is often made just like any other soft drink using sugar, carbonated water, malt extract and flavourings. Kvass is commonly served unfiltered, with the yeast still in it, which adds to its unique flavour as well as its high vitamin B content.
# Variant names
- Russian, Belarusian, Serbian and Ukrainian: квас (kvas);
- Polish: kwas chlebowy (lit. "bread leaven"),
- Lithuanian: gira;
- Estonian: kali.
## Kvass in Latvia
After the fall of the Soviet Union in 1991, the street vendors disappeared from the streets of Latvia due to new health laws that banned its sale on the street and economic disruptions forced many kvass factories to close. The Coca-Cola company moved in and quickly dominated the market for soft drinks, but in 1998 the local soft drink industry fought back by selling bottled kvass and launching an aggressive marketing campaign. This surge was further stimulated by the fact that kvass sold for about half the price of Coca-Cola. In just three years, kvass constituted as much as 30% of the soft drink market in Latvia, while the market share of Coca-Cola fell from 65% to 44%. The Coca-Cola company had losses in Latvia of about $1 million in 1999 and 2000. The situation was similar in the other Baltic countries and in Russia. Coca-Cola fought back by buying kvass manufacturers and also started making kvass at their soft drink plants.
# Similar beverages
Other beverages from around the world that are traditionally low-alcohol and lacto-fermented include:
- Kombucha
- Chicha
- Ibwatu
- Pulque
- Toddy
- Malta | Kvass
Kvass (literally "leaven"; borrowed in the 16th century from Russian квас[1]), sometimes translated into English as bread drink, is a fermented mildly alcoholic beverage made from black or rye bread. It is popular in Russia, Belarus, Ukraine and other Eastern and Central European countries as well as in all ex-Soviet states, like Uzbekistan, where one can see many kvass vendors in the streets.
The alcohol content is so low (0.05-1.44%) that it is considered acceptable for consumption by children. It is often flavoured with fruits or herbs such as strawberries or mint. Russians also use kvass for cooking a special summer cold soup, okroshka.
# History
Kvass has been a common drink in Eastern Europe since ancient times. It was at first mentioned in old-russian chronicles under 989. It has been both a commercial product and homemade. It used to be consumed widely in most Slavic countries, and in almost every city there are kvass vendors on the street.
# Manufacturing
Kvass is made by the natural fermentation of bread made from wheat, rye, or barley, and sometimes flavoured with fruit, berries, raisins or birch sap collected in the early spring.
Modern homemade kvass most often uses black or rye bread, usually dried, baked into croutons (called suharki), or fried, with the addition of sugar or fruit (e.g. apples or raisins), and with a yeast culture and zakvasska ("kvass fermentation starter").
Commercial kvass is often made just like any other soft drink using sugar, carbonated water, malt extract and flavourings. Kvass is commonly served unfiltered, with the yeast still in it, which adds to its unique flavour as well as its high vitamin B content.
# Variant names
- Russian, Belarusian, Serbian and Ukrainian: квас (kvas);
- Polish: kwas chlebowy (lit. "bread leaven"),
- Lithuanian: gira;
- Estonian: kali.
## Kvass in Latvia
After the fall of the Soviet Union in 1991, the street vendors disappeared from the streets of Latvia due to new health laws that banned its sale on the street and economic disruptions forced many kvass factories to close. The Coca-Cola company moved in and quickly dominated the market for soft drinks, but in 1998 the local soft drink industry fought back by selling bottled kvass and launching an aggressive marketing campaign. This surge was further stimulated by the fact that kvass sold for about half the price of Coca-Cola. In just three years, kvass constituted as much as 30% of the soft drink market in Latvia, while the market share of Coca-Cola fell from 65% to 44%. The Coca-Cola company had losses in Latvia of about $1 million in 1999 and 2000. The situation was similar in the other Baltic countries and in Russia. Coca-Cola fought back by buying kvass manufacturers and also started making kvass at their soft drink plants.[1][2][3][4]
# Similar beverages
Other beverages from around the world that are traditionally low-alcohol and lacto-fermented include:
- Kombucha
- Chicha
- Ibwatu
- Pulque
- Toddy
- Malta | https://www.wikidoc.org/index.php/Kvass | |
d4d720b5aa82d2a5e96c7bd616469f9e385fd4f1 | wikidoc | LACTB | LACTB
Serine beta-lactamase-like protein LACTB, mitochondrial is an enzyme that in humans is encoded by the LACTB gene. This gene encodes a 54 kDa protein sharing significant
sequence similarity to serine proteases of the penicillin binding protein and beta-lactamase superfamily occurring in bacteria.
It is involved in the regulation of the metabolic circuitry. A causal association has been found between LACTB and obesity. In breast cancer, LACTB has a tumor suppressor function by modulating lipid metabolism.
# Structure
## Gene
The LACTB gene is located at chromosome 15q22.1, consisting of 8 exons. Alternative splicing results in multiple transcript variants encoding different protein isoforms.
## Protein
LACTB shares sequence similarity to the beta-lactamase/penicillin-binding protein family of serine proteases that are involved in bacterial cell wall metabolism. The N-terminal 97 amino acid segment of LACTB does not form part of the conserved penicillin-binding protein domain and may therefore be responsible for organelle targeting.
# Function
LACTB is widely expressed in different mammalian tissues, with the predominant expression in human skeletal muscle. It localizes in the mitochondrial intermembrane space. LACTB can polymerize into stable filaments occupying the mitochondrial intermembrane space. These filaments are speculated to play a role in submitochondrial organization and therefore possibly affect mitochondrial metabolon organization.
# Clinical significance
It has been found LACTB could cause obesity through gene co-expression analysis based on data integrated from multiple sources. This has been validated in vivo through LACTB overexpression in transgenic mice, which resulted in an obese phenotype. LACTB has also been identified to be a tumor suppressor through its effect on mitochondrial phospholipid metabolism and modulation of cell differentiation state.
# Interactions
- MiR-125b-5p | LACTB
Serine beta-lactamase-like protein LACTB, mitochondrial is an enzyme that in humans is encoded by the LACTB gene.[1][2] This gene encodes a 54 kDa protein sharing significant
sequence similarity to serine proteases of the penicillin binding protein and beta-lactamase superfamily occurring in bacteria.
[3] It is involved in the regulation of the metabolic circuitry. A causal association has been found between LACTB and obesity. [4] In breast cancer, LACTB has a tumor suppressor function by modulating lipid metabolism.[5]
# Structure
## Gene
The LACTB gene is located at chromosome 15q22.1, consisting of 8 exons. Alternative splicing results in multiple transcript variants encoding different protein isoforms.
## Protein
LACTB shares sequence similarity to the beta-lactamase/penicillin-binding protein family of serine proteases that are involved in bacterial cell wall metabolism. The N-terminal 97 amino acid segment of LACTB does not form part of the conserved penicillin-binding protein domain and may therefore be responsible for organelle targeting.[3] [6]
# Function
LACTB is widely expressed in different mammalian tissues, with the predominant expression in human skeletal muscle. It localizes in the mitochondrial intermembrane space.[6] LACTB can polymerize into stable filaments occupying the mitochondrial intermembrane space. These filaments are speculated to play a role in submitochondrial organization and therefore possibly affect mitochondrial metabolon organization. [6]
# Clinical significance
It has been found LACTB could cause obesity through gene co-expression analysis based on data integrated from multiple sources. This has been validated in vivo through LACTB overexpression in transgenic mice, which resulted in an obese phenotype.[4] LACTB has also been identified to be a tumor suppressor through its effect on mitochondrial phospholipid metabolism and modulation of cell differentiation state.[7]
# Interactions
- MiR-125b-5p [8] | https://www.wikidoc.org/index.php/LACTB | |
76a9f93237d4d770bf4dcb406fa2988ae4772fd0 | wikidoc | LAMP1 | LAMP1
Lysosomal-associated membrane protein 1 (LAMP-1) also known as lysosome-associated membrane glycoprotein 1 and CD107a (Cluster of Differentiation 107a), is a protein that in humans is encoded by the LAMP1 gene. The human LAMP1 gene is located on the long arm (q) of chromosome 13 at region 3, band 4 (13q34).
Lysosomal-associated membrane protein 1 is a glycoprotein from a family of Lysosome-associated membrane glycoproteins. The LAMP-1 glycoprotein is a type I transmembrane protein which is expressed at high or medium levels in at least 76 different normal tissue cell types. It resides primarily across lysosomal membranes, and functions to provide selectins with carbohydrate ligands. CD107a has also been shown to be a marker of degranulation on lymphocytes such as CD8+ and NK cells. and may also play a role in tumor cell differentiation and metastasis.
# Structure
Residing primarily across lysosomal membranes, these glycoproteins consist of a large, highly glycosylated end with N-linked carbon chains on the luminal side of the membrane, and a short C-terminal tail exposed to the cytoplasm. The extracytoplasmic region contains a hinge-like structure which can form disulphide bridges homologous to those observed in human immunoglobulin A. Other characteristics of the structure of the LAMP-1 glycoproteins include:
- A polypeptide core of ~40kDa
- 18 {N-glycosylation} sites to help with the addition of sugar chains
- Polylactosamine attachments which protect the glyocoprotein from degradation by lysosomal proteases
- Significant quantities of polylactosaminoglycan and sialic acid to traverse the trans-Golgi cisternae.
- poly-N-acetyllactosamine groups which are involved in interactions with selectin and other glycan-binding proteins
# Function
LAMP1 and LAMP2 glycoproteins comprise 50% of all lysosomal membrane proteins, and are thought to be responsible in part for maintaining lysosomal integrity, pH and catabolism. The expression of LAMP1 and LAMP2 glycoproteins are linked, as deficiencies in LAMP1 gene will lead to increased expression of LAMP2 glycoproteins. The two are therefore thought to share similar functions in vivo. However, this makes the determining the precise function of LAMP1 difficult, because while the LAMP1 deficient phenotype is little different than the wild type due to LAMP2 up regulation, the LAMP1/LAMP2 double deficient phenotype leads to embryonic lethality.
Although the LAMP1 glycoproteins primarily reside across lysosomal membranes, in certain cases they can be expressed across the plasma membrane of the cell. Expression of LAMP1 at the cell surface can occur due to lysosomal fusion with the cell membrane. Cell surface expression of LAMP1 can serve as a ligand for selectins and help mediate cell-cell adhesion. Accordingly, cell surface expression of LAMP1 is seen in cells with migratory or invasive functions, such as cytotoxic T cells, platelets and macrophages. Cell surface expression of LAMP1 and LAMP2 is also often seen in cancer cells, particularly cancers with high metastatic potential, such as colon carcinoma and melanoma, and has been shown to correlate with their metastatic potential.
# Role in cancer
LAMP1 expression on the surface of tumor cells has been observed for a number of different cancer types, particularly in highly metastatic cancers such as pancreatic cancer, colon cancer and melanoma. The structure of LAMP1 correlates with differentiation and metastatic potential of tumor cells as it is thought to help mediate cell-cell adhesion and migration. Indeed, the adhesion of some cancer cells to the extracellular matrix is mediated by interactions between LAMP1 and LAMP2 and E-selectin and galectins, with the LAMPs serving as ligands for the cell-adhesion molecules.
Cell membrane expression of LAMP-1 observed in the following cancer types:
- Human fibrosarcoma,
- Colon adenocarcinoma,
- Melanoma,
- Pancreatic adenocarcinoma, and
- Astrocytoma. | LAMP1
Lysosomal-associated membrane protein 1 (LAMP-1) also known as lysosome-associated membrane glycoprotein 1 and CD107a (Cluster of Differentiation 107a), is a protein that in humans is encoded by the LAMP1 gene. The human LAMP1 gene is located on the long arm (q) of chromosome 13 at region 3, band 4 (13q34).
Lysosomal-associated membrane protein 1 is a glycoprotein from a family of Lysosome-associated membrane glycoproteins.[1] The LAMP-1 glycoprotein is a type I transmembrane protein[2] which is expressed at high or medium levels in at least 76 different normal tissue cell types.[3] It resides primarily across lysosomal membranes,[4] and functions to provide selectins with carbohydrate ligands.[1] CD107a has also been shown to be a marker of degranulation on lymphocytes such as CD8+ and NK cells.[5] and may also play a role in tumor cell differentiation and metastasis.
# Structure
Residing primarily across lysosomal membranes, these glycoproteins consist of a large, highly glycosylated end with N-linked carbon chains on the luminal side of the membrane, and a short C-terminal tail[2] exposed to the cytoplasm.[4] The extracytoplasmic region contains a hinge-like structure which can form disulphide bridges homologous to those observed in human immunoglobulin A.[4] Other characteristics of the structure of the LAMP-1 glycoproteins include:
- A polypeptide core of ~40kDa[4]
- 18 {N-glycosylation} sites to help with the addition of sugar chains[6]
- Polylactosamine attachments which protect the glyocoprotein from degradation by lysosomal proteases[6]
- Significant quantities of polylactosaminoglycan and sialic acid to traverse the trans-Golgi cisternae.[6]
- poly-N-acetyllactosamine groups which are involved in interactions with selectin and other glycan-binding proteins[7]
# Function
LAMP1 and LAMP2 glycoproteins comprise 50% of all lysosomal membrane proteins,[2] and are thought to be responsible in part for maintaining lysosomal integrity, pH and catabolism.[2][7] The expression of LAMP1 and LAMP2 glycoproteins are linked, as deficiencies in LAMP1 gene will lead to increased expression of LAMP2 glycoproteins.[7] The two are therefore thought to share similar functions in vivo.[2] However, this makes the determining the precise function of LAMP1 difficult, because while the LAMP1 deficient phenotype is little different than the wild type due to LAMP2 up regulation,[2][7] the LAMP1/LAMP2 double deficient phenotype leads to embryonic lethality.[7]
Although the LAMP1 glycoproteins primarily reside across lysosomal membranes, in certain cases they can be expressed across the plasma membrane of the cell.[7] Expression of LAMP1 at the cell surface can occur due to lysosomal fusion with the cell membrane.[8] Cell surface expression of LAMP1 can serve as a ligand for selectins[9][10] and help mediate cell-cell adhesion.[11] Accordingly, cell surface expression of LAMP1 is seen in cells with migratory or invasive functions, such as cytotoxic T cells, platelets and macrophages.[12] Cell surface expression of LAMP1 and LAMP2 is also often seen in cancer cells,[12][13] particularly cancers with high metastatic potential, such as colon carcinoma and melanoma,[12] and has been shown to correlate with their metastatic potential.[7]
# Role in cancer
LAMP1 expression on the surface of tumor cells has been observed for a number of different cancer types, particularly in highly metastatic cancers such as pancreatic cancer,[14][15] colon cancer[12][13] and melanoma.[12][13] The structure of LAMP1 correlates with differentiation[4][16] and metastatic potential[7] of tumor cells as it is thought to help mediate cell-cell adhesion [13] and migration.[11][14] Indeed, the adhesion of some cancer cells to the extracellular matrix is mediated by interactions between LAMP1 and LAMP2 and E-selectin and galectins, with the LAMPs serving as ligands for the cell-adhesion molecules.[13]
Cell membrane expression of LAMP-1 observed in the following cancer types:
- Human fibrosarcoma,[13]
- Colon adenocarcinoma,[13]
- Melanoma,[13]
- Pancreatic adenocarcinoma,[15] and
- Astrocytoma.[14] | https://www.wikidoc.org/index.php/LAMP1 | |
37effdc70acd160311b2f499c6c7ac6c38f00c23 | wikidoc | LAMP3 | LAMP3
Lysosome-associated membrane glycoprotein 3 (LAMP3, Lamp3) is a protein that in humans is encoded by the LAMP3 gene. It is one of the lysosome-associated membrane glycoproteins.
LAMP3 also known as DC-LAMP (Dendritic cell lysosomal associated membrane glycoprotein) is a member of the LAMP family along with LAMP1 and LAMP2, these proteins make up the members of the glycoconjugate coat present on the inside of the lysosomal membrane. In humans, this protein is almost exclusively found in mature Dendritic cells. While LAMP3 can be observed on the surface of dendritic cells, the protein is mainly found within lysosomes. LAMP3 first appears in the MHC Class II compartment and in cells aids in the identifying and processing of an antigen during an immune response. LAMP3 protein is linked with the maturation of dendritic cells, and as a marker for transformed type II pneumocytes or alveolar cells.
Studies have linked LAMP3 with the inhibition of the viral replication of Influenza A cells.
# Structure and Tissue Distribution
LAMP3 is a Type I integral membrane protein consisting of about 416 amino acid residues with about 90% of the protein located within the lumen of the lysosomes. LAMP3 has been shown to be highly expressed in dendritic cells during cell differentiation and maturation. During human fetal development, between weeks 10 and 20, LAMP3 is highly expressed in the lungs, while in normal adult tissue cells LAMP3 is expressed in the lungs, appendix, testis and lymph nodes. | LAMP3
Lysosome-associated membrane glycoprotein 3 (LAMP3, Lamp3) is a protein that in humans is encoded by the LAMP3 gene.[1][2] It is one of the lysosome-associated membrane glycoproteins.
LAMP3 also known as DC-LAMP (Dendritic cell lysosomal associated membrane glycoprotein) is a member of the LAMP family along with LAMP1 and LAMP2, these proteins make up the members of the glycoconjugate coat present on the inside of the lysosomal membrane.[3] In humans, this protein is almost exclusively found in mature Dendritic cells. While LAMP3 can be observed on the surface of dendritic cells, the protein is mainly found within lysosomes. LAMP3 first appears in the MHC Class II compartment and in cells aids in the identifying and processing of an antigen during an immune response.[4][5] LAMP3 protein is linked with the maturation of dendritic cells, and as a marker for transformed type II pneumocytes or alveolar cells.[6]
Studies have linked LAMP3 with the inhibition of the viral replication of Influenza A cells.[7]
# Structure and Tissue Distribution
LAMP3 is a Type I integral membrane protein consisting of about 416 amino acid residues with about 90% of the protein located within the lumen of the lysosomes.[5] LAMP3 has been shown to be highly expressed in dendritic cells during cell differentiation and maturation.[3] During human fetal development, between weeks 10 and 20, LAMP3 is highly expressed in the lungs, while in normal adult tissue cells LAMP3 is expressed in the lungs, appendix, testis and lymph nodes.[8] | https://www.wikidoc.org/index.php/LAMP3 | |
bae10ef943b161ccacc4815a2c33c06330985bc0 | wikidoc | LARGE | LARGE
Glycosyltransferase-like protein LARGE1 is an enzyme that in humans is encoded by the LARGE gene.
# Function
This gene, which is one of the largest in the human genome, encodes a member of the N-acetylglucosaminyltransferase gene family. The exact function of LARGE, a golgi protein, remains uncertain. It encodes a glycosyltransferase which participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. It may also be involved in the addition of a repeated disaccharide unit. Mutations in this gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Alternative splicing of this gene results in two transcript variants that encode the same protein.
LARGE may also play a role in tumor-specific genomic rearrangements. Mutations in this gene may be involved in the development and progression of meningioma through modification of ganglioside composition and other glycosylated molecules in tumor cells. | LARGE
Glycosyltransferase-like protein LARGE1 is an enzyme that in humans is encoded by the LARGE gene.[1][2][3][4]
# Function
This gene, which is one of the largest in the human genome, encodes a member of the N-acetylglucosaminyltransferase gene family. The exact function of LARGE, a golgi protein, remains uncertain.[3] It encodes a glycosyltransferase which participates in glycosylation of alpha-dystroglycan, and may carry out the synthesis of glycoprotein and glycosphingolipid sugar chains. It may also be involved in the addition of a repeated disaccharide unit. Mutations in this gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Alternative splicing of this gene results in two transcript variants that encode the same protein.[3][4]
LARGE may also play a role in tumor-specific genomic rearrangements. Mutations in this gene may be involved in the development and progression of meningioma through modification of ganglioside composition and other glycosylated molecules in tumor cells. | https://www.wikidoc.org/index.php/LARGE | |
2838b464ccdf851c971609cc338121021a47b6ad | wikidoc | LARP1 | LARP1
La-related protein 1 (LARP1) is a 150 kDa protein that in humans is encoded by the LARP1 gene. LARP1 is a novel target of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, a circuitry often hyperactivated in cancer which regulates cell growth and proliferation primarily through the regulation of protein synthesis.
# Function
LARP1 is the largest of a 7 member family of LARP proteins (others are: LARP1B, LARP3 (aka genuine La or SSB), LARP4A, LARP4B, LARP6 and LARP7). All LARP proteins, including human LARPs, contain 2 conserved regions. The first conserved region shares homology with La proteins (called the La motif, see SSB) whereas the second conserved region (called the LA- motif) is restricted to LARP proteins. LARP1 and 1B also contain a conserved "DM15 region" within their C-terminus. This region is unique and has been shown to be required for RNA-binding. Mouse Larp1 is expressed in dorsal root ganglia and spinal cord, as well as in developing organs characterized by epithelial-mesenchymal interactions. Human LARP1 is present at low levels in normal, non-embryonic cells but is highly expressed in epithelial cancers (such as ovarian, colorectal, prostate, non-small cell lung, hepatocellular and cervical cancers). Some studies have shown that high levels of LARP1 protein correlate with worse prognosis in cancer patients.
LARP1 binds to and regulates the translation of terminal oligopyrimidine motif (TOP mRNAs) and can directly interact with the 5' cap of mRNAs. It has also been shown to interact with the 3' end and coding regions (CDS) of other genes. LARP1 protein colocalizes with stress granules and P-bodies, which function in RNA storage and degradation. It has been suggested that LARP1 functions in P-bodies to attenuate the abundance of conserved Ras-MAPK mRNAs. The cluster of LARP1 homologs may function to control the expression of key developmental regulators.
Several studies have demonstrated that LARP1 deficiency selectively affects the recruitment of TOP mRNAs to polysomes . In some cancer cells, LARP1 deficiency reduces proliferation and activates apoptotic cell death. Even though a decrease abundance of proteins encoded by TOP mRNAs has been reported in LARP1 silenced cells, some researchers believe that this can be explained simply by the reduced number of TOP mRNA transcripts in LARP1-deficient cells. | LARP1
La-related protein 1 (LARP1) is a 150 kDa protein that in humans is encoded by the LARP1 gene.[1][2][1][3][2] LARP1 is a novel target of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, a circuitry often hyperactivated in cancer which regulates cell growth and proliferation primarily through the regulation of protein synthesis.
# Function
LARP1 is the largest of a 7 member family of LARP proteins (others are: LARP1B, LARP3 (aka genuine La or SSB), LARP4A, LARP4B, LARP6 and LARP7).[4] All LARP proteins, including human LARPs, contain 2 conserved regions. The first conserved region shares homology with La proteins (called the La motif, see SSB) whereas the second conserved region (called the LA- motif) is restricted to LARP proteins. LARP1 and 1B also contain a conserved "DM15 region" within their C-terminus.[5] This region is unique and has been shown to be required for RNA-binding. Mouse Larp1 is expressed in dorsal root ganglia and spinal cord, as well as in developing organs characterized by epithelial-mesenchymal interactions.[2] Human LARP1 is present at low levels in normal, non-embryonic cells but is highly expressed in epithelial cancers (such as ovarian, colorectal, prostate, non-small cell lung, hepatocellular and cervical cancers).[6][7][8][9] Some studies have shown that high levels of LARP1 protein correlate with worse prognosis in cancer patients.[10][11]
LARP1 binds to and regulates the translation of terminal oligopyrimidine motif (TOP mRNAs) and can directly interact with the 5' cap of mRNAs.[12][13] It has also been shown to interact with the 3' end and coding regions (CDS) of other genes.[12] LARP1 protein colocalizes with stress granules and P-bodies,[14] which function in RNA storage and degradation. It has been suggested that LARP1 functions in P-bodies to attenuate the abundance of conserved Ras-MAPK mRNAs. The cluster of LARP1 homologs may function to control the expression of key developmental regulators.[14]
Several studies have demonstrated that LARP1 deficiency selectively affects the recruitment of TOP mRNAs to polysomes [Reference needed]. In some cancer cells, LARP1 deficiency reduces proliferation and activates apoptotic cell death.[8] Even though a decrease abundance of proteins encoded by TOP mRNAs has been reported in LARP1 silenced cells, some researchers believe that this can be explained simply by the reduced number of TOP mRNA transcripts in LARP1-deficient cells. | https://www.wikidoc.org/index.php/LARP1 | |
5c9a739e009447e4eabb7fce3f5720ffbc34e775 | wikidoc | LASIK | LASIK
# Overview
LASIK or Lasik (laser-assisted in situ keratomileusis) is a type of refractive laser eye surgery performed by ophthalmologists for correcting myopia, hyperopia, and astigmatism. The procedure is generally preferred to photorefractive keratectomy, PRK, (also called ASA, Advanced Surface Ablation) because it requires less time for the patient's recovery, and the patient feels less pain, overall; however, there are instances where PRK/ASA is medically indicated as a better alternative to LASIK.
Many patients choose LASIK as an alternative to wearing corrective eyeglasses or contact lenses.
# Technology
The LASIK technique was made possible by the Colombia-based Spanish ophthalmologist Jose Barraquer, who, around 1950 in his clinic in Bogotá, Colombia, developed the first microkeratome, used to cut thin flaps in the cornea and alter its shape, in a procedure called keratomileusis. Stephan Schaller assisted. Barraquer also provided the knowledge about how much of the cornea had to be left unaltered to provide stable long-term results.
Later technical and procedural developments included the RK (radial keratotomy), started in the '70s in Russia by Svyatoslav Fyodorov , and the development of PRK (photorefractive keratectomy) in the '80s in Germany by Theo Seiler. RK is a procedure where radial corneal cuts are made typically using a micrometer diamond knife, and has nothing to do with LASIK
In 1968, at the Northrup Corporation Research and Technology Center of the University of California, Mani Lal Bhaumik and a group of other scientists, while working on the development of a carbon-dioxide laser, developed the Excimer laser. This formed the cornerstone for LASIK eye surgery. Dr. Bhaumik announced his discovery in May of 1973 at a meeting of the Denver Optical Society of America in Denver, Colorado. He would later patent it.
The introduction of Laser in this refractive procedure started with the developments in Laser technology by Rangaswamy Srinivasan. In 1980, Srinivasan, working at IBM Research Lab, discovered that an ultraviolet excimer laser could etch living tissue in a precise manner with no thermal damage to the surrounding area. He named the phenomenon Ablative Photodecomposition (APD).. Dr. Stephen Trokel published a paper in the American Journal of Ophthalmology in 1983, outlining the potential of using the excimer laser in refractive surgeries.
The first patent for LASIK was granted by the US Patent Office to Gholam A. Peyman, MD on June 20, 1989, US Patent #4,840,175, "METHOD FOR MODIFYING CORNEAL CURVATURE", describing the surgical procedure in which a flap is cut in the cornea and pulled back to expose the corneal bed. This exposed surface is then ablated to the desired shape with an excimer laser, following which the flap is replaced.
Using these advances in laser technology and the technical and theoretical developments in refractive surgery made since the 50's, LASIK surgery was developed in 1990 by Lucio Buratto (Italy) and Ioannis Pallikaris (Greece) as a melding of two prior techniques, keratomileusis and photorefractive keratectomy. It quickly became popular because of its greater precision and lower frequency of complications in comparison with these former two techniques.
Today, faster lasers, larger spot areas, bladeless flap incision, intraoperative pachymetry, and wavefront-optimized and -guided techniques have significantly improved the reliability of the procedure compared to that of 1991. Nonetheless, the fundamental limitations of excimer lasers and undesirable destruction of the eye's nerves have spawned research into many alternatives to "plain" LASIK, including all-femtosecond correction (Femtosecond Lenticule EXtraction, FLIVC), LASEK, Epi-LASIK, sub-Bowman’s Keratomileusis aka thin-flap LASIK, wavefront-guided PRK, and modern intraocular lenses.
# Procedure
There are several necessary preparations in the preoperative period. The operation itself is made by creating a thin flap on the eye, folding it to enable remodeling of the tissue underneath with laser. The flap is repositioned and the eye is left to heal in the postoperative period.
## Preoperative
Patients wearing soft contact lenses are usually instructed to stop wearing them approximately 5 to 21 days before surgery. One industry body recommends that patients wearing hard contact lenses should stop wearing them for a minimum of six weeks plus another six weeks for every three years the hard contacts have been worn. Before the surgery, the patient's corneas are examined with a pachymeter to determine their thickness, and with a topographer to measure their surface contour. Using low-power lasers, a topographer creates a topographic map of the cornea. This process also detects astigmatism and other irregularities in the shape of the cornea. Using this information, the surgeon calculates the amount and locations of corneal tissue to be removed during the operation. The patient typically is prescribed an antibiotic to start taking beforehand, to minimize the risk of infection after the procedure.
## Operation
The operation is performed with the patient awake and mobile; however, the patient is sometimes given a mild sedative (such as Valium) and anesthetic eye drops.
LASIK is performed in three steps. The first step is to create a flap of corneal tissue. The second step is remodeling of the cornea underneath the flap with the laser. Finally, the flap is repositioned.
### Flap creation
A corneal suction ring is applied to the eye, holding the eye in place. This step in the procedure can sometimes cause small blood vessels to burst, resulting in bleeding or subconjunctival hemorrhage into the white (sclera) of the eye, a harmless side effect that resolves within several weeks. Increased suction typically causes a transient dimming of vision in the treated eye. Once the eye is immobilized, the flap is created. This process is achieved with a mechanical microkeratome using a metal blade, or a femtosecond laser microkeratome (procedure known as IntraLASIK) that creates a series of tiny closely arranged bubbles within the cornea. A hinge is left at one end of this flap. The flap is folded back, revealing the stroma, the middle section of the cornea. The process of lifting and folding back the flap can be uncomfortable.
### Laser remodeling
The second step of the procedure is to use an excimer laser (193 nm) to remodel the corneal stroma. The laser vaporizes tissue in a finely controlled manner without damaging adjacent stroma. No burning with heat or actual cutting is required to ablate the tissue. The layers of tissue removed are tens of micrometers thick. Performing the laser ablation in the deeper corneal stroma typically provides for more rapid visual recovery and less pain, than the earlier technique photorefractive keratectomy (PRK).
During the second step, the patient's vision will become very blurry once the flap is lifted. He/she will be able to see only white light surrounding the orange light of the laser. This can be disorienting.
Currently manufactured excimer lasers use an eye tracking system that follows the patient's eye position up to 4,000 times per second, redirecting laser pulses for precise placement within the treatment zone. Typical pulses are around 1 mJ of pulse energy in 10 to 20 nanoseconds.
### Reposition of flap
After the laser has reshaped the stromal layer, the LASIK flap is carefully repositioned over the treatment area by the surgeon and checked for the presence of air bubbles, debris, and proper fit on the eye. The flap remains in position by natural adhesion until healing is completed.
## Postoperative
Patients are usually given a course of antibiotic and anti-inflammatory eye drops. These are continued in the weeks following surgery. Patients are usually told to sleep much more and are also given a darkened pair of shields to protect their eyes from bright lights and protective goggles to prevent rubbing of the eyes when asleep and to reduce dry eyes. They also have to moisturize the eyes with preservative free tears and follow directions for prescription drops. Patients should be adequately informed by their surgeons of the importance of proper post-operative care to minimize the risk of post-surgical complications.
# Higher-order aberrations
Higher-order aberrations are visual problems not captured in a traditional eye exam which tests only for acuteness of vision. Severe aberrations can effectively cause significant vision impairment. These aberrations include starbursts, ghosting, halos, double vision, and a number of other post-operative complications listed below.
Concern has long plagued the tendency of refractive surgeries to induce higher-order aberration not correctable by traditional contacts or glasses. The advancement of LASIK technique and technologies has helped reduce the risk of clinically significant visual impairment after the surgery. One of the major discoveries was the correlation between pupil size and aberrations: Effectively, the larger the pupil size, the greater the risk of aberrations. This correlation is the result of the irregularity between the untouched part of the cornea and the reshaped part. Daytime post-lasik vision is optimal, since the pupil is smaller than the LASIK flap. But at night, the pupil may expand such that light passes through the edge of the LASIK flap into the pupil which gives rise to many aberrations. There are other currently unknown factors in addition to pupil size that also affect higher order aberrations.
In extreme cases, where ideal technique was not followed and before key advances, some people could suffer rather debilitating symptoms including serious loss of contrast sensitivity in poor lighting situations.
Over time, most of the attention has been focused on spherical aberration. LASIK and PRK tend to induce spherical aberration, because of the tendency of the laser to undercorrect as it moves outward from the center of the treatment zone. This is really a significant issue for only large corrections. There is some thought if the lasers were simply programmed to adjust for this tendency, no significant spherical aberration would be induced. Hence, in eyes with little existing higher order aberrations, wavefront-optimized LASIK rather than wavefront-guided LASIK may well be the future.
In any case, higher order aberrations are measured in µm (micrometers) on the wavescan taken during the pre-op examination, while the smallest beam size of FDA approved lasers is about 1000 times larger, at 0.65 mm. Thus imperfections are inherent in the procedure and a reason why patients experience halo, glare, and starburst even with small naturally dilated pupils in dim lighting.
## Wavefront-guided LASIK
Wavefront-guided LASIK is a variation of LASIK surgery where, rather than applying a simple correction of focusing power to the cornea (as in traditional LASIK), an ophthalmologist applies a spatially varying correction, guiding the computer-controlled excimer laser with measurements from a wavefront sensor. The goal is to achieve a more optically perfect eye, though the final result still depends on the physician's success at predicting changes which occur during healing. In older patients though, scattering from microscopic particles plays a major role and may exceed any benefit from wavefront correction. Hence, patients expecting so-called "super vision" from such procedures may be disappointed. However, while unproven, surgeons claim patients are generally more satisfied with this technique than with previous methods, particularly regarding lowered incidence of "halos", the visual artifact caused by spherical aberration induced in the eye by earlier methods.
# Complications
The most common complication following LASIK has been the the development of "dry eyes", which is most common when the flap is thicker and created with a metal microkeratome. According to an American Journal of Ophthalmology study of March 2006, the incidence rate of dry eyes from LASIK after the six month post operative healing period was 36.36%.. The FDA (Food and Drugs Administration) website states that "dry eyes" may be permanent. However, the risk of developing dry eyes is currently much lower with the use of femtosecond lasers which create thin, planar flaps. Additionally, patients can be pretreated with topical cyclosporine, as well as continue this medication postoperatively, to improve the tear film and reduce the risk of developing dry eye.
The risk for a patient of suffering from disturbing visual side effects such as halos, double vision (ghosting), loss of contrast sensitivity (foggy vision) and glare after LASIK depends on the degree of ametropia before the laser eye surgery and other risk factors. For this reason, it is important to take into account the individual risk potential of a patient and not just the average probability for all patients. The following are some of the more frequently reported complications of LASIK:
- Surgery induced dry eyes
- Overcorrection or undercorrection
- Visual acuity fluctuation
- Halos or starbursts around light sources at night
- Light sensitivity
- Ghost images or double vision
- Wrinkles in flap (striae)
- Decentered ablation
- Debris or growth under flap
- Thin or buttonhole flap
- Induced astigmatism
- Corneal ectasia
- Floaters
- Epithelium erosion
- Posterior vitreous detachment
- Macular hole
Complications due to LASIK have been classified as those that occur due to preoperative, intraoperative, early postoperative, or late postoperative sources:
## Intraoperative complications
- The incidence of flap complications has been estimated to be 0.244%. Flap complications (such as displaced flaps or folds in the flaps that necessitate repositioning, diffuse lamellar keratitis, and epithelial ingrowth) are common in lamellar corneal surgeries but rarely lead to permanent visual acuity loss; the incidence of these microkeratome-related complications decreases with increased physician experience. According to proponents of such techniques, this risk is further reduced by the use of IntraLasik and other non-microkeratome related approaches, although this is not proven and carries its own set of risks of complications from the IntraLasik procedure.
- A slipped flap (a corneal flap that detaches from the rest of the cornea) is one of the most common complications. The chances of this are greatest immediately after surgery, so patients typically are advised to go home and sleep to let the flap heal. Patients are usually given sleep goggles or eye shields to wear for several nights to prevent them from dislodging the flap in their sleep. A faster operation may decrease the chance of this complication, as there is less time for the flap to dry.
- Flap interface particles are another finding whose clinical significance is undetermined. A Finnish study found that particles of various sizes and reflectivity were clinically visible in 38.7% of eyes examined via slit lamp biomicroscopy, but apparent in 100% of eyes using confocal microscopy.
## Early postoperative complications
- The incidence of diffuse lamellar keratitis (DLK), also known as the Sands of Sahara syndrome, has been estimated at 2.3%. When diagnosed and appropriately treated, DLK resolves with no lasting vision limitation.
- The incidence of infection responsive to treatment has been estimated at 0.4%. Infection under the corneal flap is possible. It is also possible that a patient has the genetic condition keratoconus that causes the cornea to thin after surgery. Although this condition is screened in the preoperative exam, it is possible in rare cases (about 1 in 5,000) for the condition to remain dormant until later in life (the mid-40s). If this occurs, the patient may need rigid gas permeable contact lenses, Intrastromal Corneal Ring Segments (Intacs), Corneal Collagen Crosslinking with Riboflavin or a corneal transplant.
- The incidence of persistent dry eye has been estimated to be as high as 28% in Asian eyes and 5% in Caucasian eyes. Nerve fibers in the cornea are important for stimulating tear production. A year after LASIK, subbasal nerve fiber bundles remain reduced by more than half. Some patients experience reactive tearing, in part to compensate for chronic decreased basal wetting tear production.
- The incidence of subconjunctival hemorrhage has been estimated at 10.5% .
## Late postoperative complications
- The incidence of epithelial ingrowth has been estimated at 0.1%.
- Glare is another commonly reported complication of those who have had LASIK.
- Halos or starbursts around bright lights at night are caused by the irregularity between the lasered part and the untouched part. It is not practical to perform the surgery so that it covers the width of the pupil at full dilation at night, and the pupil may expand so that light passes through the edge of the flap into the pupil. In daytime, the pupil is smaller than the edge. Modern equipment is better suited to treat those with large pupils, and responsible physicians will check for them during examination.
- Late traumatic flap dislocations have been reported 1–7 years post-LASIK.
## Other
Lasik and other forms of laser refractive surgery (i.e. PRK, LASEK and Epi-LASEK) change the dynamics of the cornea. These changes make it difficult for your optometrist and ophthalmologist to accurately measure your intraocular pressure, essential in glaucoma screening and treatment. The changes also affect the calculations used to select the correct intraocular lens implant when you have cataract surgery. This is known to ophthalmologists as "refractive surprise." The correct intraocular pressure and intraocular lens power can be calculated if you can provide your eye care professional with your preoperative, operative and postoperative eye measurements.
Although there have been improvements in LASIK technology, a large body of conclusive evidence on the chances of long-term complications is not yet established. Also, there is a small chance of complications, such as haziness, halo, or glare, some of which may be irreversible because the LASIK eye surgery procedure is irreversible.
The incidence of macular hole has been estimated at 0.2 percent to 0.3 percent. The incidence of retinal detachment has been estimated at 0.36 percent. The incidence of choroidal neovascularization has been estimated at 0.33 percent. The incidence of uveitis has been estimated at 0.18 percent
Although the cornea usually is thinner after LASIK, because of the removal of part of the stroma, refractive surgeons strive to maintain a minimum thickness to avoid structurally weakening the cornea. Decreased atmospheric pressure at higher altitudes has not been demonstrated as extremely dangerous to the eyes of LASIK patients. However, some mountain climbers have experienced a myopic shift at extreme altitudes. There are no published reports documenting scuba diving-related complications after LASIK.
In situ keratomileusis effected at a later age increases the incidence of corneal higher-order wavefront aberrations. Conventional eyeglasses do not correct higher order aberrations.
Microfolding has been reported as "an almost unavoidable complication of LASIK" whose "clinical significance appears negligible."
Blepharitis, or inflammation of the eyelids with crusting of the eyelashes, may increase the risk of infection or inflammation of the cornea after LASIK.
Myopic (nearsighted) people who are close to the age (mid- to late-forties) when they will require either reading glasses or bifocal eyeglasses may find that they still require reading glasses despite having undergone refractive LASIK surgery. Myopic people generally require reading glasses or bifocal eyeglasses at a later age than people who are emmetropic (those who see without eyeglasses), but this benefit is lost if they undergo LASIK. This is not a complication but an expected result of the physical laws of optics. Although there is currently no method to completely eradicate the need for reading glasses in this group, it may be minimized by performing a variation of the LASIK procedure called "slight monovision." In this procedure, which is performed exactly like distance-vision-correction LASIK, the dominant eye is set for distance vision, while the non-dominant eye is set to the prescription of the patient's reading glasses. This allows the patient to achieve a similar effect as wearing bifocals. The majority of patients tolerate this procedure very well and do not notice any shift between near and distance viewing, although a small portion of the population has trouble adjusting to the monovision effect. This can be tested for several days prior to surgery by wearing contact lenses that mimic the monovision effect.
## Factors affecting surgery
Typically, the cornea is avascular because it must be transparent to function normally, and its cells absorb oxygen from the tear film. Thus, low-oxygen-permeable contact lenses reduce the cornea's oxygen absorption, sometimes resulting in corneal neovascularization—the growth of blood vessels into the cornea. This causes a slight lengthening of inflammation duration and healing time and some pain during surgery, because of greater bleeding.
Although some contact lenses (notably modern RGP and soft silicone hydrogel lenses) are made of materials with greater oxygen permeability that help reduce the risk of corneal neovascularization, patients considering LASIK are warned to avoid over-wearing their contact lenses. Usually, it is recommended that they discontinue wearing contact lenses days or weeks before the LASIK eye surgery.
A 2004 Wake Forest University study established that heat and humidity affect LASIK surgery results, both during the procedure and in the two weeks before the surgery.
## Age considerations
New advances in eyesight corrective surgery are providing consumers greater choices. Patients in their 40s or 50s who are considering LASIK surgery to improve their vision might want to consider to be evaluated for implantable lenses as well. "Early signs of a cataract might argue for surgery and implantation of multifocal lenses instead."
The FDA has approved LASIK for age 18 and over. More importantly the person's eye needs to be stable for two years prior to surgery.
# Patient satisfaction
The surveys determining patient satisfaction with LASIK have found most patients satisfied, with satisfaction range being 92–98 percent. A meta-analysis dated March 2008 performed by the American Society of Cataract and Refractive Surgery over 3,000 peer-reviewed articles published over the past 10 years in clinical journals from around the world, including 19 studies comprising 2,200 patients that looked directly at satisfaction, revealed a 95.4 percent patient satisfaction rate among LASIK patients worldwide.
Some patients with poor outcomes from LASIK surgical procedures report a significantly reduced quality of life because of vision problems. Patients who have suffered LASIK complications have created websites and discussion forums to educate the public about the risks, where prospective and past patients can discuss the surgery. In 1999, Surgical Eyes was founded in New York Cityby RK patient Ron Link as a resource for patients with complications of LASIK and other refractive surgeries. Other patient-founded websites to assist those with complications are LaserMyEye founded in 2004 and
Vision Surgery Rehab in 2005.Most experienced and reputable clinics will do a full-dilated medical eye exam prior to surgery and give adequate post-operative patient education care to minimize the risk of a negative outcome.
For best results, Dr. Steven Schallhorn, an ophthalmologist who oversaw the US Navy's refractive surgery program and whose research partly influenced the Navy's decision to allow its aviators to get Lasik, recommends patients seek out what's called "all-laser Lasik" combined with "wavefront-guided" software.
The FDA website on LASIK clearly states: "Before undergoing a refractive procedure, you should carefully weigh the risks and benefits based on your own personal value system, and try to avoid being influenced by friends that have had the procedure or doctors encouraging you to do so." As such, prospective patients still need to fully understand all the potential issues and complications, as satisfaction is directly related to expectation.
The FDA received 140 "negative reports relating to LASIK" for the time period 1998–2006.
# Safety and efficacy
The reported figures for safety and efficacy are open to interpretation. In 2003, the Medical Defence Union (MDU), the largest insurer for doctors in the United Kingdom, reported a 166 percent increase in claims involving laser eye surgery; however, the MDU averred that these claims resulted primarily from patients' unrealistic expectations of LASIK rather than faulty surgery. A 2003 study, reported in the medical journal Ophthalmology, found that nearly 18 percent of treated patients and 12 percent of treated eyes needed retreatment. The authors concluded that higher initial corrections, astigmatism, and older age are risk factors for LASIK retreatment.
In 2004, the British National Health Service's National Institute for Health and Clinical Excellence (NICE) considered a systematic review of four randomized controlled trials before issuing guidance for the use of LASIK within the NHS. Regarding the procedure's efficacy, NICE reported, "Current evidence on LASIK for the treatment of refractive errors suggests that it is effective in selected patients with mild or moderate short-sightedness," but that "evidence is weaker for its effectiveness in severe short-sightedness and long-sightedness." Regarding the procedure's safety, NICE reported that "there are concerns about the procedure's safety in the long term and current evidence does not appear adequate to support its use within the NHS without special arrangements for consent and for audit or research."
Leading refractive surgeons in the United Kingdom and United States, including at least one author of a study cited in the report, believe NICE relied on information that is severely dated and weakly researched.
On October 10, 2006, WebMD reported that statistical analysis revealed that contact lens wear infection risk is greater than the infection risk from LASIK. Daily contact lens wearers have a 1-in-100 chance of developing a serious, contact lens-related eye infection in 30 years of use, and a 1-in-2,000 chance of suffering significant vision loss as a result of infection. The researchers calculated the risk of significant vision loss consequence of LASIK surgery to be closer to 1-in-10,000 cases.
On February 21, 2007, the Food and Drug Administration (FDA) issued a Class I recall of the LADAR-6000 surgical laser, manufactured by Alcon. The recall was because the algorithm used to calculate the laser treatment left some patients with inaccurate surgical outcomes that could not be re-treated with additional surgery. | LASIK
# Overview
LASIK or Lasik (laser-assisted in situ keratomileusis) is a type of refractive laser eye surgery performed by ophthalmologists for correcting myopia, hyperopia, and astigmatism.[1] The procedure is generally preferred to photorefractive keratectomy, PRK, (also called ASA, Advanced Surface Ablation) because it requires less time for the patient's recovery, and the patient feels less pain, overall; however, there are instances where PRK/ASA is medically indicated as a better alternative to LASIK.
Many patients choose LASIK as an alternative to wearing corrective eyeglasses or contact lenses.
# Technology
The LASIK technique was made possible by the Colombia-based Spanish ophthalmologist Jose Barraquer, who, around 1950 in his clinic in Bogotá, Colombia, developed the first microkeratome, used to cut thin flaps in the cornea and alter its shape, in a procedure called keratomileusis. Stephan Schaller assisted. Barraquer also provided the knowledge about how much of the cornea had to be left unaltered to provide stable long-term results.
Later technical and procedural developments included the RK (radial keratotomy), started in the '70s in Russia by Svyatoslav Fyodorov , and the development of PRK (photorefractive keratectomy) in the '80s in Germany by Theo Seiler. RK is a procedure where radial corneal cuts are made typically using a micrometer diamond knife, and has nothing to do with LASIK
In 1968, at the Northrup Corporation Research and Technology Center of the University of California, Mani Lal Bhaumik and a group of other scientists, while working on the development of a carbon-dioxide laser, developed the Excimer laser. This formed the cornerstone for LASIK eye surgery. Dr. Bhaumik announced his discovery in May of 1973 at a meeting of the Denver Optical Society of America in Denver, Colorado. He would later patent it. [1]
The introduction of Laser in this refractive procedure started with the developments in Laser technology by Rangaswamy Srinivasan. In 1980, Srinivasan, working at IBM Research Lab, discovered that an ultraviolet excimer laser could etch living tissue in a precise manner with no thermal damage to the surrounding area. He named the phenomenon Ablative Photodecomposition (APD).[2]. Dr. Stephen Trokel published a paper in the American Journal of Ophthalmology in 1983, outlining the potential of using the excimer laser in refractive surgeries.
The first patent for LASIK was granted by the US Patent Office to Gholam A. Peyman, MD on June 20, 1989, US Patent #4,840,175, "METHOD FOR MODIFYING CORNEAL CURVATURE", describing the surgical procedure in which a flap is cut in the cornea and pulled back to expose the corneal bed. This exposed surface is then ablated to the desired shape with an excimer laser, following which the flap is replaced.
Using these advances in laser technology and the technical and theoretical developments in refractive surgery made since the 50's, LASIK surgery was developed in 1990 by Lucio Buratto (Italy) and Ioannis Pallikaris (Greece) as a melding of two prior techniques, keratomileusis and photorefractive keratectomy. It quickly became popular because of its greater precision and lower frequency of complications in comparison with these former two techniques.
Today, faster lasers, larger spot areas, bladeless flap incision, intraoperative pachymetry, and wavefront-optimized and -guided techniques have significantly improved the reliability of the procedure compared to that of 1991. Nonetheless, the fundamental limitations of excimer lasers and undesirable destruction of the eye's nerves have spawned research into many alternatives to "plain" LASIK, including all-femtosecond correction (Femtosecond Lenticule EXtraction, FLIVC), LASEK, Epi-LASIK, sub-Bowman’s Keratomileusis aka thin-flap LASIK, wavefront-guided PRK, and modern intraocular lenses.
# Procedure
There are several necessary preparations in the preoperative period. The operation itself is made by creating a thin flap on the eye, folding it to enable remodeling of the tissue underneath with laser. The flap is repositioned and the eye is left to heal in the postoperative period.
## Preoperative
Patients wearing soft contact lenses are usually instructed to stop wearing them approximately 5 to 21 days before surgery. One industry body recommends that patients wearing hard contact lenses should stop wearing them for a minimum of six weeks plus another six weeks for every three years the hard contacts have been worn. [3] Before the surgery, the patient's corneas are examined with a pachymeter to determine their thickness, and with a topographer to measure their surface contour. Using low-power lasers, a topographer creates a topographic map of the cornea. This process also detects astigmatism and other irregularities in the shape of the cornea. Using this information, the surgeon calculates the amount and locations of corneal tissue to be removed during the operation. The patient typically is prescribed an antibiotic to start taking beforehand, to minimize the risk of infection after the procedure.
## Operation
The operation is performed with the patient awake and mobile; however, the patient is sometimes given a mild sedative (such as Valium) and anesthetic eye drops.
LASIK is performed in three steps. The first step is to create a flap of corneal tissue. The second step is remodeling of the cornea underneath the flap with the laser. Finally, the flap is repositioned.
### Flap creation
A corneal suction ring is applied to the eye, holding the eye in place. This step in the procedure can sometimes cause small blood vessels to burst, resulting in bleeding or subconjunctival hemorrhage into the white (sclera) of the eye, a harmless side effect that resolves within several weeks. Increased suction typically causes a transient dimming of vision in the treated eye. Once the eye is immobilized, the flap is created. This process is achieved with a mechanical microkeratome using a metal blade, or a femtosecond laser microkeratome (procedure known as IntraLASIK) that creates a series of tiny closely arranged bubbles within the cornea.[4] A hinge is left at one end of this flap. The flap is folded back, revealing the stroma, the middle section of the cornea. The process of lifting and folding back the flap can be uncomfortable.
### Laser remodeling
The second step of the procedure is to use an excimer laser (193 nm) to remodel the corneal stroma. The laser vaporizes tissue in a finely controlled manner without damaging adjacent stroma. No burning with heat or actual cutting is required to ablate the tissue. The layers of tissue removed are tens of micrometers thick. Performing the laser ablation in the deeper corneal stroma typically provides for more rapid visual recovery and less pain, than the earlier technique photorefractive keratectomy (PRK).
During the second step, the patient's vision will become very blurry once the flap is lifted. He/she will be able to see only white light surrounding the orange light of the laser. This can be disorienting.
Currently manufactured excimer lasers use an eye tracking system that follows the patient's eye position up to 4,000 times per second, redirecting laser pulses for precise placement within the treatment zone. Typical pulses are around 1 mJ of pulse energy in 10 to 20 nanoseconds.[2]
### Reposition of flap
After the laser has reshaped the stromal layer, the LASIK flap is carefully repositioned over the treatment area by the surgeon and checked for the presence of air bubbles, debris, and proper fit on the eye. The flap remains in position by natural adhesion until healing is completed.
## Postoperative
Patients are usually given a course of antibiotic and anti-inflammatory eye drops. These are continued in the weeks following surgery. Patients are usually told to sleep much more and are also given a darkened pair of shields to protect their eyes from bright lights and protective goggles to prevent rubbing of the eyes when asleep and to reduce dry eyes. They also have to moisturize the eyes with preservative free tears and follow directions for prescription drops. Patients should be adequately informed by their surgeons of the importance of proper post-operative care to minimize the risk of post-surgical complications.
# Higher-order aberrations
Higher-order aberrations are visual problems not captured in a traditional eye exam which tests only for acuteness of vision. Severe aberrations can effectively cause significant vision impairment. These aberrations include starbursts, ghosting, halos, double vision, and a number of other post-operative complications listed below.
Concern has long plagued the tendency of refractive surgeries to induce higher-order aberration not correctable by traditional contacts or glasses. The advancement of LASIK technique and technologies has helped reduce the risk of clinically significant visual impairment after the surgery. One of the major discoveries was the correlation between pupil size and aberrations:[3] Effectively, the larger the pupil size, the greater the risk of aberrations. This correlation is the result of the irregularity between the untouched part of the cornea and the reshaped part. Daytime post-lasik vision is optimal, since the pupil is smaller than the LASIK flap. But at night, the pupil may expand such that light passes through the edge of the LASIK flap into the pupil which gives rise to many aberrations. There are other currently unknown factors in addition to pupil size that also affect higher order aberrations.
In extreme cases, where ideal technique was not followed and before key advances, some people could suffer rather debilitating symptoms including serious loss of contrast sensitivity in poor lighting situations.
Over time, most of the attention has been focused on spherical aberration. LASIK and PRK tend to induce spherical aberration, because of the tendency of the laser to undercorrect as it moves outward from the center of the treatment zone. This is really a significant issue for only large corrections. There is some thought if the lasers were simply programmed to adjust for this tendency, no significant spherical aberration would be induced. Hence, in eyes with little existing higher order aberrations, wavefront-optimized LASIK rather than wavefront-guided LASIK may well be the future.
In any case, higher order aberrations are measured in µm (micrometers) on the wavescan taken during the pre-op examination, while the smallest beam size of FDA approved lasers is about 1000 times larger, at 0.65 mm. Thus imperfections are inherent in the procedure and a reason why patients experience halo, glare, and starburst even with small naturally dilated pupils in dim lighting.
## Wavefront-guided LASIK
Wavefront-guided LASIK[4] is a variation of LASIK surgery where, rather than applying a simple correction of focusing power to the cornea (as in traditional LASIK), an ophthalmologist applies a spatially varying correction, guiding the computer-controlled excimer laser with measurements from a wavefront sensor. The goal is to achieve a more optically perfect eye, though the final result still depends on the physician's success at predicting changes which occur during healing. In older patients though, scattering from microscopic particles plays a major role and may exceed any benefit from wavefront correction. Hence, patients expecting so-called "super vision" from such procedures may be disappointed. However, while unproven, surgeons claim patients are generally more satisfied with this technique than with previous methods, particularly regarding lowered incidence of "halos", the visual artifact caused by spherical aberration induced in the eye by earlier methods.
# Complications
The most common complication following LASIK has been the the development of "dry eyes", which is most common when the flap is thicker and created with a metal microkeratome. According to an American Journal of Ophthalmology study of March 2006, the incidence rate of dry eyes from LASIK after the six month post operative healing period was 36.36%.[5]. The FDA (Food and Drugs Administration) website states that "dry eyes" may be permanent[5]. However, the risk of developing dry eyes is currently much lower with the use of femtosecond lasers which create thin, planar flaps. Additionally, patients can be pretreated with topical cyclosporine, as well as continue this medication postoperatively, to improve the tear film and reduce the risk of developing dry eye.
The risk for a patient of suffering from disturbing visual side effects such as halos, double vision (ghosting), loss of contrast sensitivity (foggy vision) and glare after LASIK depends on the degree of ametropia before the laser eye surgery and other risk factors.[6] For this reason, it is important to take into account the individual risk potential of a patient and not just the average probability for all patients.[7] The following are some of the more frequently reported complications of LASIK[8][6]:
- Surgery induced dry eyes
- Overcorrection[9] or undercorrection
- Visual acuity fluctuation
- Halos[10] or starbursts[11] around light sources at night
- Light sensitivity
- Ghost images[12] or double vision
- Wrinkles in flap (striae)[13]
- Decentered ablation
- Debris or growth under flap
- Thin or buttonhole flap [14]
- Induced astigmatism
- Corneal ectasia
- Floaters
- Epithelium erosion
- Posterior vitreous detachment[15]
- Macular hole[16]
Complications due to LASIK have been classified as those that occur due to preoperative, intraoperative, early postoperative, or late postoperative sources:[17]
## Intraoperative complications
- The incidence of flap complications has been estimated to be 0.244%.[18] Flap complications (such as displaced flaps or folds in the flaps that necessitate repositioning, diffuse lamellar keratitis, and epithelial ingrowth) are common in lamellar corneal surgeries[19] but rarely lead to permanent visual acuity loss; the incidence of these microkeratome-related complications decreases with increased physician experience.[20][21] According to proponents of such techniques, this risk is further reduced by the use of IntraLasik and other non-microkeratome related approaches, although this is not proven and carries its own set of risks of complications from the IntraLasik procedure.
- A slipped flap (a corneal flap that detaches from the rest of the cornea) is one of the most common complications. The chances of this are greatest immediately after surgery, so patients typically are advised to go home and sleep to let the flap heal. Patients are usually given sleep goggles or eye shields to wear for several nights to prevent them from dislodging the flap in their sleep. A faster operation may decrease the chance of this complication, as there is less time for the flap to dry.
- Flap interface particles are another finding whose clinical significance is undetermined.[22] A Finnish study found that particles of various sizes and reflectivity were clinically visible in 38.7% of eyes examined via slit lamp biomicroscopy, but apparent in 100% of eyes using confocal microscopy.[22]
## Early postoperative complications
- The incidence of diffuse lamellar keratitis (DLK)[7], also known as the Sands of Sahara syndrome, has been estimated at 2.3%.[23] When diagnosed and appropriately treated, DLK resolves with no lasting vision limitation.
- The incidence of infection responsive to treatment has been estimated at 0.4%.[23] Infection under the corneal flap is possible. It is also possible that a patient has the genetic condition keratoconus that causes the cornea to thin after surgery. Although this condition is screened in the preoperative exam, it is possible in rare cases (about 1 in 5,000) for the condition to remain dormant until later in life (the mid-40s). If this occurs, the patient may need rigid gas permeable contact lenses, Intrastromal Corneal Ring Segments (Intacs),[24] Corneal Collagen Crosslinking with Riboflavin[25] or a corneal transplant.
- The incidence of persistent dry eye has been estimated to be as high as 28% in Asian eyes and 5% in Caucasian eyes.[26] Nerve fibers in the cornea are important for stimulating tear production. A year after LASIK, subbasal nerve fiber bundles remain reduced by more than half.[27] Some patients experience reactive tearing, in part to compensate for chronic decreased basal wetting tear production.
- The incidence of subconjunctival hemorrhage has been estimated at 10.5% [23](according to a study undertaken in China; thus results may not be generally applicable due to racial and geographic factors).
## Late postoperative complications
- The incidence of epithelial ingrowth has been estimated at 0.1%.[23]
- Glare is another commonly reported complication of those who have had LASIK.[28]
- Halos or starbursts around bright lights at night are caused by the irregularity between the lasered part and the untouched part. It is not practical to perform the surgery so that it covers the width of the pupil at full dilation at night, and the pupil may expand so that light passes through the edge of the flap into the pupil.[29] In daytime, the pupil is smaller than the edge. Modern equipment is better suited to treat those with large pupils, and responsible physicians will check for them during examination.
- Late traumatic flap dislocations have been reported 1–7 years post-LASIK.[30]
## Other
Lasik and other forms of laser refractive surgery (i.e. PRK, LASEK and Epi-LASEK) change the dynamics of the cornea. These changes make it difficult for your optometrist and ophthalmologist to accurately measure your intraocular pressure, essential in glaucoma screening and treatment. The changes also affect the calculations used to select the correct intraocular lens implant when you have cataract surgery. This is known to ophthalmologists as "refractive surprise." The correct intraocular pressure and intraocular lens power can be calculated if you can provide your eye care professional with your preoperative, operative and postoperative eye measurements.
Although there have been improvements in LASIK technology[31][32][33], a large body of conclusive evidence on the chances of long-term complications is not yet established. Also, there is a small chance of complications, such as haziness, halo, or glare, some of which may be irreversible because the LASIK eye surgery procedure is irreversible.
The incidence of macular hole has been estimated at 0.2 percent[16] to 0.3 percent.[34] The incidence of retinal detachment has been estimated at 0.36 percent.[34] The incidence of choroidal neovascularization has been estimated at 0.33 percent.[34] The incidence of uveitis has been estimated at 0.18 percent[35]
Although the cornea usually is thinner after LASIK, because of the removal of part of the stroma, refractive surgeons strive to maintain a minimum thickness to avoid structurally weakening the cornea. Decreased atmospheric pressure at higher altitudes has not been demonstrated as extremely dangerous to the eyes of LASIK patients. However, some mountain climbers have experienced a myopic shift at extreme altitudes.[36][37] There are no published reports documenting scuba diving-related complications after LASIK.[38]
In situ keratomileusis effected at a later age increases the incidence of corneal higher-order wavefront aberrations.[39][40] Conventional eyeglasses do not correct higher order aberrations.
Microfolding has been reported as "an almost unavoidable complication of LASIK" whose "clinical significance appears negligible."[22]
Blepharitis, or inflammation of the eyelids with crusting of the eyelashes, may increase the risk of infection or inflammation of the cornea after LASIK.[41]
Myopic (nearsighted) people who are close to the age (mid- to late-forties) when they will require either reading glasses or bifocal eyeglasses may find that they still require reading glasses despite having undergone refractive LASIK surgery. Myopic people generally require reading glasses or bifocal eyeglasses at a later age than people who are emmetropic (those who see without eyeglasses), but this benefit is lost if they undergo LASIK. This is not a complication but an expected result of the physical laws of optics. Although there is currently no method to completely eradicate the need for reading glasses in this group, it may be minimized by performing a variation of the LASIK procedure called "slight monovision." In this procedure, which is performed exactly like distance-vision-correction LASIK, the dominant eye is set for distance vision, while the non-dominant eye is set to the prescription of the patient's reading glasses. This allows the patient to achieve a similar effect as wearing bifocals. The majority of patients tolerate this procedure very well and do not notice any shift between near and distance viewing, although a small portion of the population has trouble adjusting to the monovision effect. This can be tested for several days prior to surgery by wearing contact lenses that mimic the monovision effect.
## Factors affecting surgery
Typically, the cornea is avascular because it must be transparent to function normally, and its cells absorb oxygen from the tear film. Thus, low-oxygen-permeable contact lenses reduce the cornea's oxygen absorption, sometimes resulting in corneal neovascularization—the growth of blood vessels into the cornea. This causes a slight lengthening of inflammation duration and healing time and some pain during surgery, because of greater bleeding.
Although some contact lenses (notably modern RGP and soft silicone hydrogel lenses) are made of materials with greater oxygen permeability that help reduce the risk of corneal neovascularization, patients considering LASIK are warned to avoid over-wearing their contact lenses. Usually, it is recommended that they discontinue wearing contact lenses days or weeks before the LASIK eye surgery.
A 2004 Wake Forest University study established that heat and humidity affect LASIK surgery results, both during the procedure and in the two weeks before the surgery.[42]
## Age considerations
New advances in eyesight corrective surgery are providing consumers greater choices. Patients in their 40s or 50s who are considering LASIK surgery to improve their vision might want to consider to be evaluated for implantable lenses as well. "Early signs of a cataract might argue for surgery and implantation of multifocal lenses instead." [43]
The FDA has approved LASIK for age 18 and over[44]. More importantly the person's eye needs to be stable for two years prior to surgery.
# Patient satisfaction
The surveys determining patient satisfaction with LASIK have found most patients satisfied, with satisfaction range being 92–98 percent.[28][45][46][47] A meta-analysis dated March 2008 performed by the American Society of Cataract and Refractive Surgery over 3,000 peer-reviewed articles published over the past 10 years in clinical journals from around the world, including 19 studies comprising 2,200 patients that looked directly at satisfaction, revealed a 95.4 percent patient satisfaction rate among LASIK patients worldwide. [48]
Some patients with poor outcomes from LASIK surgical procedures report a significantly reduced quality of life because of vision problems. Patients who have suffered LASIK complications have created websites and discussion forums to educate the public about the risks, where prospective and past patients can discuss the surgery. In 1999, Surgical Eyes[49] was founded[50] in New York City[51]by RK patient Ron Link[52] as a resource for patients with complications of LASIK and other refractive surgeries. Other patient-founded websites to assist those with complications are LaserMyEye[53] founded [54] in 2004 and
Vision Surgery Rehab [55] [56] in 2005.[57]Most experienced and reputable clinics will do a full-dilated medical eye exam prior to surgery and give adequate post-operative patient education care to minimize the risk of a negative outcome.
For best results, Dr. Steven Schallhorn, an ophthalmologist who oversaw the US Navy's refractive surgery program and whose research partly influenced the Navy's decision to allow its aviators to get Lasik, recommends patients seek out what's called "all-laser Lasik" combined with "wavefront-guided" software.[58][59]
The FDA website on LASIK clearly states: "Before undergoing a refractive procedure, you should carefully weigh the risks and benefits based on your own personal value system, and try to avoid being influenced by friends that have had the procedure or doctors encouraging you to do so."[60] As such, prospective patients still need to fully understand all the potential issues and complications, as satisfaction is directly related to expectation.
The FDA received 140 "negative reports relating to LASIK" for the time period 1998–2006.[61]
# Safety and efficacy
The reported figures for safety and efficacy are open to interpretation. In 2003, the Medical Defence Union (MDU), the largest insurer for doctors in the United Kingdom, reported a 166 percent increase in claims involving laser eye surgery; however, the MDU averred that these claims resulted primarily from patients' unrealistic expectations of LASIK rather than faulty surgery.[62] A 2003 study, reported in the medical journal Ophthalmology, found that nearly 18 percent of treated patients and 12 percent of treated eyes needed retreatment.[63] The authors concluded that higher initial corrections, astigmatism, and older age are risk factors for LASIK retreatment.
In 2004, the British National Health Service's National Institute for Health and Clinical Excellence (NICE) considered a systematic review of four randomized controlled trials[64][65] before issuing guidance for the use of LASIK within the NHS.[66] Regarding the procedure's efficacy, NICE reported, "Current evidence on LASIK for the treatment of refractive errors suggests that it is effective in selected patients with mild or moderate short-sightedness," but that "evidence is weaker for its effectiveness in severe short-sightedness and long-sightedness." Regarding the procedure's safety, NICE reported that "there are concerns about the procedure's safety in the long term and current evidence does not appear adequate to support its use within the NHS without special arrangements for consent and for audit or research."
Leading refractive surgeons in the United Kingdom and United States, including at least one author of a study cited in the report, believe NICE relied on information that is severely dated and weakly researched.[67][68]
On October 10, 2006, WebMD reported that statistical analysis revealed that contact lens wear infection risk is greater than the infection risk from LASIK.[69] Daily contact lens wearers have a 1-in-100 chance of developing a serious, contact lens-related eye infection in 30 years of use, and a 1-in-2,000 chance of suffering significant vision loss as a result of infection. The researchers calculated the risk of significant vision loss consequence of LASIK surgery to be closer to 1-in-10,000 cases.
On February 21, 2007, the Food and Drug Administration (FDA) issued a Class I recall of the LADAR-6000 surgical laser, manufactured by Alcon.[70] [71] The recall was because the algorithm used to calculate the laser treatment left some patients with inaccurate surgical outcomes that could not be re-treated with additional surgery. | https://www.wikidoc.org/index.php/LASIK | |
5836a647ebfffb0ffbdc986e4d47ba2cc2d5f130 | wikidoc | LECT2 | LECT2
Leukocyte cell-derived chemotaxin-2 (LECT2) is a protein first described in 1996 as a chemotactic factor for neutrophils, i.e. it stimulated human neutrophils to move directionally in an in vitro assay system. The protein was detected in and purified from cultures of Phytohaemagglutinin-activated human T-cell leukemia SKW-3 cells. Subsequent studies have defined LECT2 as a hepatokine, i.e. a substance made and released into the circulation by liver hepatocyte cells that regulates the function of other cells: it is a hepatocyte-derived, hormone-like, signaling protein.
LECT2 has been detected in the blood and other tissues in a wide range of animal species from zebrafish to man. Furthermore, its levels in these tissues often change as a function of various diseases. These findings indicate that LECT is an evolutionary conserved protein, has one or more important functions, and may be involved in various diseases. However, LECT2's relationships to these diseases requires much further study before they can be regarded as established and clinically useful. One exception to this, however, is its proven role in amyloidosis. LECT2 is one of the more common causes of systemic (as opposed to localized) amyloidosis in North America as well as certain other ethnically-rich locations.
LECT2 and its gene, LECT2, are currently areas of active research that seek to implicate them as contributors to, markers for the presence of, and/or prognostic indicators for the severity of not only amyloidosis but also osteoarthritis, rheumatoid arthritis, and other types of inflammation-related disorders; the metabolic syndrome and diabetes; and various types of liver disease.
# Gene
The human LECT2 gene, LECT2, is located on the long, i.e, "q", arm of chromosome 5 at position q31.1 (notated as 5q31.1). This location is close to several immune modulating genes including interleukins 3, 5, and 9 and granulocyte-macrophage colony stimulating factor. LECT2 is conserved in zebrafish, chichen, rat, mouse, cow. dog, Rhesus monkey, and chimpanzee. Human LECT2 is composed of 4 exons, 3 introns, and ~8,000 base pairs. The gene has numerous single nucleotide variants as well as other variations, some of which have been associated with human disease. Human LECT2 has several different transcriptional initiation sights and codes for a mRNA composed of 1,000 to 1,300 ribonucleotides. mRNA for LECT2 is highly expressed in liver tissue and expressed at far lower levels in a wide range of other tssues.
# Protein
Human LECT2 is a secreted, 16 kilodalton protein. The secreted protein consists of 133`amino acids (mouse Lect2 consists of two varieties a typical 151 amino acid protein and an atypical 132 amino acid protein). Its structure is similar to that of the M23 family of metalloendopeptidases. Unlike this family of peptidases, however, LECT2 has not been found to possess enzymatic activity and does not appear to share any functions with M23 metalloendopeptidases.
LECT2 protein is widely expressed in vascular tissues, smooth muscle cells, adipocytes, cerebral neurons, apical squamous epithelia, parathyroid tissues, the epithelial cells of sweat and sebaceous glands, Hassall bodies, and monocytes. When these cells or tissues are subjected to inflammatory, fibrotic, and other insults, they commonly reduce their expression of LECT2. The liver hepatocyte is considered to be the source of the LECT2 circulating in blood. However, its expression in these cells is extremely low or undetectable even though these cells express very high levels of LECT2 mRNA. This implies that hepatocytes secrete LECT2 almost immediately after they make it. Using very sensitive methods, LECT2 protein can also be detected at low levels in the endothelial cells of hepatic arteries and veins including central veins. Several cell types or tissues, e.g. osteoblasts, chondrocytes, cardiac tissue, gastrointestinal smooth muscle cells, and epithelial cells of some tissues normally do not express LECT2 but do so under a variety of disease conditions.
# Disease associations
## LECT2 amyloidosis
LECT2 amyloidosis (ALECT2) was the third most common (~3% of total) cause of amyloidosis in a series of >4,000 individuals studied at the Mayo Clinic in the United States. However, LECT2 amyloidosis has a strong ethnic bias, afflicting particularly Mexicans and to a lesser extent, non-Mexican Hispanics. Hispanics made an important contribution to the Mayo Clinic's rate of LECT2 amyloidosis. LECT2 amyloidosis also has an increased incidence in Punjabis, South Asians, First Nations people of British Columbia, Native Americans, and Egyptians. In Egyptians, LECT2 is second most common cause of renal amyloidosis, accounting for nearly 31% of all cases. LECT2 amyloidosis is likely to be a far less common cause of systemic amyloidosis in populations containing fewer numbers of individuals of the cited ethnic groups. On the other hand, LECT2 amyloidosis represents an important but at present very much under-recognized cause of chronic kidney disease in the cited ethnic groups and, possibly, other ethnic groups yet to be deteremined.
It has been found repeatedly that the mere presence of LECT2 amyloid tissue deposits does not necessarily indicate the presence of LECT2 amyloidosis disease. For example, autopsy studies find that up to 3.1% of Hispanics have these deposits in their kidneys but no history of signs or symptoms that could be attributed to LECT2 amyloidosis. This finding suggests that the LECT2 amyloidosis and its ethnic bias reflect multiple poorly understood factors.
### Pathophysiology
While the pathogenesis of LECT2 amyloidosis is unclear, the intact LECT2 protein may have a tendency to fold abnormally thereby forming non-soluble fibrils that are deposited in tissues. It has been suggested that individuals with the disease have an increase in LECT2 production and/or a decrease in LECT2 catabolism (i.e. breakdown) which leads to its tissue deposition. However, there appears to be clear genetic variations which lead LECT2 tissue deposition. While studies to date have failed to obtain evidence for LECT2 gene mutations in the disorder, most cases examined in the United States are associated with a particular homozygous single nucleotide polymorphism (i.e. SNP) in the LECT2 gene. This SNP occurs in exon 3 at codon 58 of the gene, contains a guanine rather than adenine nucleotide at this site, and consequently codes for the amino acid valine rather than isoleucine. It is suggested although not yet proven that this Val58Ile variant of LECT2 has a propensity to fold abnormally and therefore deposits in tissues. The Val58Ile LECT2 variant is common in Hispanics and appears to be the cause of their high incidence of LECT2 amyloidosis. Nonetheless, not all homozygous carriers of the variant ever exhibit LECT2 amyloidosis.
A second SNP commonly found in Mexicans occurs at codon 172 of the LECT2 gene. This variant is homozygous for a G nucleotide at this codon position and has been associated with an increased incidence of LECT2 amyloidosis. A reason for this association has not yet been proposed.
### Presentation
LECT2 amyloidosis presents with renal disease that in general is slowly progressive and at the time of presentation is of varying severity ranging from early findings of proteinuria or small elevations in blood urea nitrogen and/or creatinine to findings of end stage renal disease. At presentation, many individuals are elderly and suffer serious kidney dysfunction. They may have histological evidence of LECT2 amyloid deposition in the liver, lung, spleen, kidney, and adrenal glands of rarely show any symptoms or signs attributable to dysfunction in these organs. Unlike many other forms of systemic amyloidosis, LECT2 deposition has not been reported to be deposited in the myocardium or brain of afflicted individuals. Thus, LECT2 amyloidosis, while classified as a form of systemic amyloidosis, is almost exclusively manifested clinically as renal amyloidosis.
### Diagnosis
LECT amyloidosis is diagnosed by two findings: a) histological evidence of Congo red staining material deposited in the interstitial, mesangial, glomerular, and/or vascular areas of the kidney and b) the identification of these deposits as containing mainly LECT2 as identified by proteomics methodologies. Kidney biopsy shows the presence of LECT2-based amyloid predominantly in the renal cortex interstitium, glomeruli, and arterioles.
### Treatment
There has too little experience on the treatment of LECT2 amyloidosis (ALECT2) to establish recommendations. There is no recommended specific treatment for LECT2 amyloidosis other than support of kidney function and dialysis. It is important to accurately diagnose ALECT2-based amyloid disease in order to avoid treatment for other forms of amyloidosis.
### Prognosis
Based on studies conducted in the United States, the prognosis for individuals with LECT2 amyloidosis is guarded, particularly because they are elderly and their kidney disease is usually well-advanced at the time of presentation.
## Rheumatoid arthritis
Studies conducted in a mouse model of rheumatoid arthritis indicate that the LECT2 protein suppresses the inflammatory component of this disorder. In human studies, the Val58Ile variant of LECT2 protein which has been associated with the development of LECT2 amyloidosis in Hispanics has also been associated with rheumatoid arthritis. That is, individuals homozygous for the gene making the Val58Ile variant of LECT2 have a small but significant increase in both the incidence and severity of this disease based on a study conducted in Japan. An increase in the severity and joint destruction of rheumatoid arthritis in humans was confirmed in a separate study conducted in Germany. These studies suggest that LECT2 normally functions to suppress the development and/or severity of human rheumatoid arthritis and that the Val58Ile variant of LECT2 is less effective in doing so.
## Osteoarthritis
In a model of osteoarthritis, mice made deficient in LECT2 using a gene knockout method developed more severe osteoarthritis induced by anti-type II collagen antibodies and lipopolysaccharide. The effect was reversed by administering human LECT2 to the animals. A study conducted in Japan found that the expression levels of LECT2 were significantly higher in cartilage of osteoarthritic individuals than in control patients suggesting that LECT2 may be a useful biomarker for the disease.
## Sepsis
In mouse models of bacterial sepsis caused by of E. coli, P. aeruginosa, and ligation followed by puncture of the cecum, the administration of human LECT2 improved survival. LECTT2 acted by directly stimulating the CD209 receptor on mouse macrophages thereby mobilizing their protective functions. Knockout of the Lect2 gene in mice increase the mortality caused by staphylococcal enterotoxin A; human LECT2 reduced this morality increase. Blood levels of LECT2 in patients suffering bacterial sepsis correlated inversely with the severity of systemic inflammation suggesting that LECT2 blood levels may be a reliable diagnostic indicator of human inflammatory diseases.
## Diabetes
Deletion of the Lect2 gene in mice improves peripheral glucose entry into tissues. These studies suggest that mouse Lect2 suppresses insulin signaling in skeletal muscle but not adipose or liver tissues of Lect2-deficient mice and thereby may contribute to the development of insulin resistance. Indeed, serum levels of LECT2 are increased in animal models of insulin-resistant diabetes as well as in individual diabetics demonstrating insulin resistance. These data suggest that inhibiting LECT2 production or action may be clinically useful means for treating diabetes. In support of this notion, Gemigliptin, an anti-diabetic drug, has been shown reduce insulin resistance and concurrently inhibit Lect2 production in a mouse model of dietary-induces insulin resistance. Studies conducted on cultured myocytes, a form of muscle cell, indicates that LECT2 impairs insulin signaling by activating a c-Jun N-terminal kinases cell signaling pathway.
## Metabolic syndrome
Mice made deficient in the Lect2 gene were compared to wild-type mice in a model of high fatty acid diet-induced obesity and the metabolic syndrome. Lect2-deficient mice appeared to be protected from developing certain characteristics of the metabolic syndrome: they exhibited less weight gain; lower blood glucose and insulin levels following feeding; and better results for glucose and insulin tolerance tests. In a study of 200 individuals in Japan, serum LECT2 levels correlated positively with (i.e. increased in proportion to increases in) several clinical features of the metabolic syndrome viz., body mass index, waist circumference, systolic blood pressure, selenoprotein P serum levels, and hemoglobin A1c blood levels. Levels of LECT2 are also elevated in individuals not only with diagnosed metabolic syndrome but also with a characteristic of and possible precursor to the metabolic syndrome, non-alcoholic fatty liver disease. LEPT2 has been suggested to be a potential therapeutic target for treating the metabolic syndrome.
## Cancer
Circulating levels of LECT2 are elevated in >90% of individuals with hepatoblastoma and >20% of individuals with Hepatocellular carcinoma. In the latter form of liver cancer, LECT2 levels increase with increasingly poor prognostic stages of the disease and therefore may prove to be valuable prognostic markers. | LECT2
Leukocyte cell-derived chemotaxin-2 (LECT2) is a protein first described in 1996 as a chemotactic factor for neutrophils, i.e. it stimulated human neutrophils to move directionally in an in vitro assay system. The protein was detected in and purified from cultures of Phytohaemagglutinin-activated human T-cell leukemia SKW-3 cells.[1] Subsequent studies have defined LECT2 as a hepatokine, i.e. a substance made and released into the circulation by liver hepatocyte cells that regulates the function of other cells: it is a hepatocyte-derived, hormone-like, signaling protein.[2][3]
LECT2 has been detected in the blood and other tissues in a wide range of animal species from zebrafish to man. Furthermore, its levels in these tissues often change as a function of various diseases. These findings indicate that LECT is an evolutionary conserved protein, has one or more important functions, and may be involved in various diseases. However, LECT2's relationships to these diseases requires much further study before they can be regarded as established and clinically useful. One exception to this, however, is its proven role in amyloidosis. LECT2 is one of the more common causes of systemic (as opposed to localized) amyloidosis in North America as well as certain other ethnically-rich locations.[4]
LECT2 and its gene, LECT2, are currently areas of active research that seek to implicate them as contributors to, markers for the presence of, and/or prognostic indicators for the severity of not only amyloidosis but also osteoarthritis, rheumatoid arthritis, and other types of inflammation-related disorders; the metabolic syndrome and diabetes; and various types of liver disease.[2]
# Gene
The human LECT2 gene, LECT2, is located on the long, i.e, "q", arm of chromosome 5 at position q31.1 (notated as 5q31.1). This location is close to several immune modulating genes including interleukins 3, 5, and 9 and granulocyte-macrophage colony stimulating factor. LECT2 is conserved in zebrafish, chichen, rat, mouse, cow. dog, Rhesus monkey, and chimpanzee. Human LECT2 is composed of 4 exons, 3 introns, and ~8,000 base pairs. The gene has numerous single nucleotide variants as well as other variations, some of which have been associated with human disease. Human LECT2 has several different transcriptional initiation sights and codes for a mRNA composed of 1,000 to 1,300 ribonucleotides. mRNA for LECT2 is highly expressed in liver tissue and expressed at far lower levels in a wide range of other tssues.[2][5]
# Protein
Human LECT2 is a secreted, 16 kilodalton protein. The secreted protein consists of 133`amino acids (mouse Lect2 consists of two varieties a typical 151 amino acid protein and an atypical 132 amino acid protein). Its structure is similar to that of the M23 family of metalloendopeptidases. Unlike this family of peptidases, however, LECT2 has not been found to possess enzymatic activity and does not appear to share any functions with M23 metalloendopeptidases.[2][6]
LECT2 protein is widely expressed in vascular tissues, smooth muscle cells, adipocytes, cerebral neurons, apical squamous epithelia, parathyroid tissues, the epithelial cells of sweat and sebaceous glands, Hassall bodies, and monocytes. When these cells or tissues are subjected to inflammatory, fibrotic, and other insults, they commonly reduce their expression of LECT2. The liver hepatocyte is considered to be the source of the LECT2 circulating in blood. However, its expression in these cells is extremely low or undetectable even though these cells express very high levels of LECT2 mRNA. This implies that hepatocytes secrete LECT2 almost immediately after they make it. Using very sensitive methods, LECT2 protein can also be detected at low levels in the endothelial cells of hepatic arteries and veins including central veins. Several cell types or tissues, e.g. osteoblasts, chondrocytes, cardiac tissue, gastrointestinal smooth muscle cells, and epithelial cells of some tissues normally do not express LECT2 but do so under a variety of disease conditions.[2]
# Disease associations
## LECT2 amyloidosis
LECT2 amyloidosis (ALECT2) was the third most common (~3% of total) cause of amyloidosis in a series of >4,000 individuals studied at the Mayo Clinic in the United States. However, LECT2 amyloidosis has a strong ethnic bias, afflicting particularly Mexicans and to a lesser extent, non-Mexican Hispanics. Hispanics made an important contribution to the Mayo Clinic's rate of LECT2 amyloidosis. LECT2 amyloidosis also has an increased incidence in Punjabis, South Asians, First Nations people of British Columbia, Native Americans, and Egyptians. In Egyptians, LECT2 is second most common cause of renal amyloidosis, accounting for nearly 31% of all cases. LECT2 amyloidosis is likely to be a far less common cause of systemic amyloidosis in populations containing fewer numbers of individuals of the cited ethnic groups.[4][7][8] On the other hand, LECT2 amyloidosis represents an important but at present very much under-recognized cause of chronic kidney disease in the cited ethnic groups and, possibly, other ethnic groups yet to be deteremined.[9]
It has been found repeatedly that the mere presence of LECT2 amyloid tissue deposits does not necessarily indicate the presence of LECT2 amyloidosis disease. For example, autopsy studies find that up to 3.1% of Hispanics have these deposits in their kidneys but no history of signs or symptoms that could be attributed to LECT2 amyloidosis. This finding suggests that the LECT2 amyloidosis and its ethnic bias reflect multiple poorly understood factors.[2]
### Pathophysiology
While the pathogenesis of LECT2 amyloidosis is unclear, the intact LECT2 protein may have a tendency to fold abnormally thereby forming non-soluble fibrils that are deposited in tissues. It has been suggested that individuals with the disease have an increase in LECT2 production and/or a decrease in LECT2 catabolism (i.e. breakdown) which leads to its tissue deposition. However, there appears to be clear genetic variations which lead LECT2 tissue deposition. While studies to date have failed to obtain evidence for LECT2 gene mutations in the disorder, most cases examined in the United States are associated with a particular homozygous single nucleotide polymorphism (i.e. SNP) in the LECT2 gene. This SNP occurs in exon 3 at codon 58 of the gene, contains a guanine rather than adenine nucleotide at this site, and consequently codes for the amino acid valine rather than isoleucine. It is suggested although not yet proven that this Val58Ile variant of LECT2 has a propensity to fold abnormally and therefore deposits in tissues. The Val58Ile LECT2 variant is common in Hispanics and appears to be the cause of their high incidence of LECT2 amyloidosis. Nonetheless, not all homozygous carriers of the variant ever exhibit LECT2 amyloidosis.[2]
A second SNP commonly found in Mexicans occurs at codon 172 of the LECT2 gene. This variant is homozygous for a G nucleotide at this codon position and has been associated with an increased incidence of LECT2 amyloidosis. A reason for this association has not yet been proposed.[2][10]
### Presentation
LECT2 amyloidosis presents with renal disease that in general is slowly progressive and at the time of presentation is of varying severity ranging from early findings of proteinuria or small elevations in blood urea nitrogen and/or creatinine to findings of end stage renal disease. At presentation, many individuals are elderly and suffer serious kidney dysfunction. They may have histological evidence of LECT2 amyloid deposition in the liver, lung, spleen, kidney, and adrenal glands of rarely show any symptoms or signs attributable to dysfunction in these organs. Unlike many other forms of systemic amyloidosis, LECT2 deposition has not been reported to be deposited in the myocardium or brain of afflicted individuals. Thus, LECT2 amyloidosis, while classified as a form of systemic amyloidosis, is almost exclusively manifested clinically as renal amyloidosis.[4]
### Diagnosis
LECT amyloidosis is diagnosed by two findings: a) histological evidence of Congo red staining material deposited in the interstitial, mesangial, glomerular, and/or vascular areas of the kidney and b) the identification of these deposits as containing mainly LECT2 as identified by proteomics methodologies. Kidney biopsy shows the presence of LECT2-based amyloid predominantly in the renal cortex interstitium, glomeruli, and arterioles.[4][10]
### Treatment
There has too little experience on the treatment of LECT2 amyloidosis (ALECT2) to establish recommendations. There is no recommended specific treatment for LECT2 amyloidosis other than support of kidney function and dialysis. It is important to accurately diagnose ALECT2-based amyloid disease in order to avoid treatment for other forms of amyloidosis.[10]
### Prognosis
Based on studies conducted in the United States, the prognosis for individuals with LECT2 amyloidosis is guarded, particularly because they are elderly and their kidney disease is usually well-advanced at the time of presentation.[10]
## Rheumatoid arthritis
Studies conducted in a mouse model of rheumatoid arthritis indicate that the LECT2 protein suppresses the inflammatory component of this disorder. In human studies, the Val58Ile variant of LECT2 protein which has been associated with the development of LECT2 amyloidosis in Hispanics has also been associated with rheumatoid arthritis. That is, individuals homozygous for the gene making the Val58Ile variant of LECT2 have a small but significant increase in both the incidence and severity of this disease based on a study conducted in Japan. An increase in the severity and joint destruction of rheumatoid arthritis in humans was confirmed in a separate study conducted in Germany. These studies suggest that LECT2 normally functions to suppress the development and/or severity of human rheumatoid arthritis and that the Val58Ile variant of LECT2 is less effective in doing so.[2]
## Osteoarthritis
In a model of osteoarthritis, mice made deficient in LECT2 using a gene knockout method developed more severe osteoarthritis induced by anti-type II collagen antibodies and lipopolysaccharide. The effect was reversed by administering human LECT2 to the animals. A study conducted in Japan found that the expression levels of LECT2 were significantly higher in cartilage of osteoarthritic individuals than in control patients suggesting that LECT2 may be a useful biomarker for the disease.[2]
## Sepsis
In mouse models of bacterial sepsis caused by of E. coli, P. aeruginosa, and ligation followed by puncture of the cecum, the administration of human LECT2 improved survival. LECTT2 acted by directly stimulating the CD209 receptor on mouse macrophages thereby mobilizing their protective functions. Knockout of the Lect2 gene in mice increase the mortality caused by staphylococcal enterotoxin A; human LECT2 reduced this morality increase. Blood levels of LECT2 in patients suffering bacterial sepsis correlated inversely with the severity of systemic inflammation suggesting that LECT2 blood levels may be a reliable diagnostic indicator of human inflammatory diseases.[2]
## Diabetes
Deletion of the Lect2 gene in mice improves peripheral glucose entry into tissues. These studies suggest that mouse Lect2 suppresses insulin signaling in skeletal muscle but not adipose or liver tissues of Lect2-deficient mice and thereby may contribute to the development of insulin resistance. Indeed, serum levels of LECT2 are increased in animal models of insulin-resistant diabetes as well as in individual diabetics demonstrating insulin resistance. These data suggest that inhibiting LECT2 production or action may be clinically useful means for treating diabetes.[3] In support of this notion, Gemigliptin, an anti-diabetic drug, has been shown reduce insulin resistance and concurrently inhibit Lect2 production in a mouse model of dietary-induces insulin resistance.[2] Studies conducted on cultured myocytes, a form of muscle cell, indicates that LECT2 impairs insulin signaling by activating a c-Jun N-terminal kinases cell signaling pathway.[11]
## Metabolic syndrome
Mice made deficient in the Lect2 gene were compared to wild-type mice in a model of high fatty acid diet-induced obesity and the metabolic syndrome. Lect2-deficient mice appeared to be protected from developing certain characteristics of the metabolic syndrome: they exhibited less weight gain; lower blood glucose and insulin levels following feeding; and better results for glucose and insulin tolerance tests. In a study of 200 individuals in Japan, serum LECT2 levels correlated positively with (i.e. increased in proportion to increases in) several clinical features of the metabolic syndrome viz., body mass index, waist circumference, systolic blood pressure, selenoprotein P serum levels, and hemoglobin A1c blood levels.[2] Levels of LECT2 are also elevated in individuals not only with diagnosed metabolic syndrome but also with a characteristic of and possible precursor to the metabolic syndrome, non-alcoholic fatty liver disease.[11][12] LEPT2 has been suggested to be a potential therapeutic target for treating the metabolic syndrome.[2]
## Cancer
Circulating levels of LECT2 are elevated in >90% of individuals with hepatoblastoma and >20% of individuals with Hepatocellular carcinoma. In the latter form of liver cancer, LECT2 levels increase with increasingly poor prognostic stages of the disease and therefore may prove to be valuable prognostic markers.[2] | https://www.wikidoc.org/index.php/LECT2 | |
e2960ed4966b09da42168a2d0c0e093e80bc96a6 | wikidoc | LEKTI | LEKTI
Lympho-epithelial Kazal-type-related inhibitor (LEKTI) also known as serine protease inhibitor Kazal-type 5 (SPINK5) is a protein that in humans is encoded by the SPINK5 gene.
# Structure and function
LEKTI is a large multidomain serine protease inhibitor expressed in stratified epithelial tissue. It consists of 15 domains that are cleaved into smaller, functional fragments by the protease furin. Only two of these domains (2 and 15) contain 6 evenly spaced cysteines responsible for 3 intramolecular disulfide bonds characteristic of Kazal-type related inhibitors. The remaining domains contain 4 cysteines. These disulfide bonds force the molecule into a rigid conformation that enables the protein to interact with a target protease via an extended beta-sheet. All domains (excepting 1, 2 and 15) contain an arginine at P1, indicating trypsin-like proteases are the likely targets.
In the epidermis, LEKTI is implicated in the regulation of desquamation via its ability to selectively inhibit KLK5, KLK7 and KLK14. Recombinant full length LEKTI inhibits the exogenous serine proteases trypsin, plasmin, subtilisin A, cathepsin G and human neutrophil elastase.
LEKTI may play a role in skin and hair morphogenesis and anti-inflammatory and/or antimicrobial protection of mucous epithelia.
# Gene
SPINK5 is a member of a gene family cluster located on chromosome 5q32, which encode inhibitors of serine proteases. This includes other epidermal proteins SPINK6 and LEKTI-2 (SPINK9). The SPINK5 gene is 61 kb in length and contains 33 exons. Alternative processing of SPINK5 results in the formation of three different gene products, which have been identified in differentiated keratinocytes.
# Clinical significance
Mutations in the SPINK5 gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy. | LEKTI
Lympho-epithelial Kazal-type-related inhibitor (LEKTI) also known as serine protease inhibitor Kazal-type 5 (SPINK5) is a protein that in humans is encoded by the SPINK5 gene.[1][2]
# Structure and function
LEKTI is a large multidomain serine protease inhibitor expressed in stratified epithelial tissue. It consists of 15 domains that are cleaved into smaller, functional fragments by the protease furin. Only two of these domains (2 and 15) contain 6 evenly spaced cysteines responsible for 3 intramolecular disulfide bonds characteristic of Kazal-type related inhibitors. The remaining domains contain 4 cysteines.[3] These disulfide bonds force the molecule into a rigid conformation that enables the protein to interact with a target protease via an extended beta-sheet. All domains (excepting 1, 2 and 15) contain an arginine at P1, indicating trypsin-like proteases are the likely targets.[3]
In the epidermis, LEKTI is implicated in the regulation of desquamation via its ability to selectively inhibit KLK5, KLK7 and KLK14.[4] Recombinant full length LEKTI inhibits the exogenous serine proteases trypsin, plasmin, subtilisin A, cathepsin G and human neutrophil elastase.[5]
LEKTI may play a role in skin and hair morphogenesis and anti-inflammatory and/or antimicrobial protection of mucous epithelia.[2]
# Gene
SPINK5 is a member of a gene family cluster located on chromosome 5q32,[6] which encode inhibitors of serine proteases. This includes other epidermal proteins SPINK6 and LEKTI-2 (SPINK9). The SPINK5 gene is 61 kb in length and contains 33 exons.[3] Alternative processing of SPINK5 results in the formation of three different gene products, which have been identified in differentiated keratinocytes.[7]
# Clinical significance
Mutations in the SPINK5 gene may result in Netherton syndrome, a disorder characterized by ichthyosis, defective cornification, and atopy.[2] | https://www.wikidoc.org/index.php/LEKTI | |
82031c9318da58b7c9b07d0d9f9719c805ea6576 | wikidoc | LENG9 | LENG9
Leukocyte Receptor Cluster Member 9 (LENG 9) is an uncharacterized protein encoded by the LENG9 gene. In humans, LENG9 is predicted to play a role in fertility and reproductive disorders associated with female endometrium structures.
# Gene
## Location
LENG9 is located at 19q13.42 on chromosome 19, spanning the sense strand (-) from 54,461,796 bp to 54,463,711 bp. The LENG9 gene is 1,930 base pairs in length and contains one exon.
## Gene Neighborhood
Genes LENG8-AS1 and CDC42EP5 neighbor LENG9 on chromosome 19. CDC42EP5 extends over the same region of LENG9 while LENG8-AS1 is located to the left of both genes. TTYH1 and LENG8 are also found in the same gene neighborhood but are located on the opposite strand.
## Expression
LENG9 is highly expressed (75-100%) in skeletal muscles and part of fetal liver tissues while ubiquitous expression of LENG9 is moderate (50-75%) in all other tissues observed. Human expression of LENG9 is observed in the cervix, lung, and placenta of adults. The gene is also expressed in disease states including lung tumors and primitive neuroectodermal tumors, usually found in children or young adults. However, LENG9 is not expressed during the juvenile stage of development.
## Promotor
The promotor region is predicted to be 1101 base pairs in length. The transcriptional start site found in this region is located 119 bp upstream of the start codon as well as an in-frame stop codon at 1087 bp to 1089 bp.
# mRNA Transcript
## Splice Variants
In humans, LENG9 has two mRNA unspliced transcript variants. Variant (1) is the longest and most conserved transcript of the gene and is made up of one exon that is composed of 1,919 bp.
# Protein
## General Properties
LENG9 is 501 amino acids in length, with a predicted molecular weight of 53.2 kDa. The isoelectric point of LENG9 protein is predicted to be 7.7. No known transmembrane sequences were found for LENG9.
## Composition
Analysis of the LENG9 protein was performed against the "human" database, which indicated a higher frequency of alanine and proline amino acids than of that of a normal human protein. Inversely, an abnormally lower frequency of aspartate, isoleucine, methionine, asparagine, serine, and tyrosine amino acids were detected.
## Structure
The secondary structure of LENG9 is predicted to be composed of alpha-helices and beta-sheets throughout the sequence. The tertiary structure of LENG9 is displayed in the image to the right.
## Sub-cellular localization
A strong signal peptide detected in the mitochondrion region (0.788) suggests that the LENG9 protein localizes in the mitochondrial matrix. However, further analysis among other mammal orthologs predicted sub-cellular localization in the cytoplasm and nuclear localization for Danio rerio.
## Post Translational Modifications
LENG9 is predicted to undergo post-translational modifications such as phosphorylation, N-terminal acetylation, sumoylation, and C-terminal Glycosylphosphatidylinositol (GPI) anchor modification.
### Phosphorylation
LENG9 contains numerous phosphorylation sites distributed in the protein sequence, as show in the diagram to the right. These sites include casein kinase 2 (CK2), cAMP-dependent protein kinase (PKA), protein kinase C (PKC), ataxia-telangiectasia mutated kinase (ATM), cyclin-dependent kinase 5 (CDK5), and casein kinase 1 (CK1).
### N-terminal Acetylation
There is one predicted N-terminal acetylation site found in the protein LENG9 at the serine amino acid position 3.
### Sumoylation
There are two predicted sumoylation sites within LENG9 at position 82 and 452 on lysine residues.
### C-Terminal GPI Anchor Modification
A C-terminal GPI modification site was found on the glycine residue at position 486.
## Domains and Motifs
There are 3 conserved domains in LENG9. The metal-ion binding zinc finger domain ZnF_C3H1 is found from amino acid 46 to 61. LENG9 also has a domain of unknown function belonging to the domain family DUF504, that spans from amino acid 109 to 160. The last conserved domain spans from amino acid 320 to 500 and is known as AKAP7 2'5' RNA ligase-like domain (AKAP7_NLS).
Conserved WD40 repeats are found in LENG9, spanning from amino acid 98 to 159. This motif is characterized by beta-propeller structures in the tertiary structure.
## Protein Interactions
LENG9 is found to interact with the C9ORF41 protein that encodes methyltransferase, involved in converting carnosine to anserine present in skeletal muscle. Another interactor is CDC5L, which is a positive regulator for the cell cycle for phase G2 to M transition. FOXS1 is another interacting protein that functions as a transcriptional repressor to suppress promotors such as FASLG, FOXO3, and FOXO4.
# Clinical Significance
## Disease Association
The LENG9 gene was found to be up-regulated and expressed in endothelial endometrium (hEECs) tissues during various stages of the menstrual/reproductive cycle when transfected with the RNA gene, miR-30d. As ectopic over-expression of miR-30d in hEECs is observed to affect cancer-associated genes, LENG9 is predicted to play a role in reproductive and endocrine system disorders.
## Fertility
Analysis of endometrial receptivity using miRNA of receptive and prereceptive endometrium from fertile women also indicated significant up-regulation of miR-30d. Consequently, the induced expression of LENG9 from miR-30d transfection suggests a possible relationship between the LENG9 gene and female fertility functions.
# Homology
## Evolution
Comparison of the LENG9 protein was conducted against fibrinogen and cytochrome C to observe the rate of evolutionary change. The relatively fast rate of change in LENG9 compared to that of other proteins suggests that the gene is adaptive for vital cell structures and functions.
## Paralogs
There are no known paralogs for LENG9.
## Orthologs
LENG9 is highly conserved in mammals and bony fish such as the zebrafish. It is also conserved a in few reptiles and amphibians. The gene is not present in invertebrates, birds, bacteria, or fungi | LENG9
Leukocyte Receptor Cluster Member 9 (LENG 9) is an uncharacterized protein encoded by the LENG9 gene.[1][2] In humans, LENG9 is predicted to play a role in fertility and reproductive disorders associated with female endometrium structures.[3][4]
# Gene
## Location
LENG9 is located at 19q13.42 on chromosome 19, spanning the sense strand (-) from 54,461,796 bp to 54,463,711 bp.[5] The LENG9 gene is 1,930 base pairs in length and contains one exon.[1][2]
## Gene Neighborhood
Genes LENG8-AS1 and CDC42EP5 neighbor LENG9 on chromosome 19.[2] CDC42EP5 extends over the same region of LENG9 while LENG8-AS1 is located to the left of both genes.[5] TTYH1 and LENG8 are also found in the same gene neighborhood but are located on the opposite strand.
## Expression
LENG9 is highly expressed (75-100%) in skeletal muscles and part of fetal liver tissues while ubiquitous expression of LENG9 is moderate (50-75%) in all other tissues observed.[6][7] Human expression of LENG9 is observed in the cervix, lung, and placenta of adults.[8] The gene is also expressed in disease states including lung tumors and primitive neuroectodermal tumors, usually found in children or young adults. However, LENG9 is not expressed during the juvenile stage of development.[8]
## Promotor
The promotor region is predicted to be 1101 base pairs in length.[9] The transcriptional start site found in this region is located 119 bp upstream of the start codon[1] as well as an in-frame stop codon at 1087 bp to 1089 bp.[5]
# mRNA Transcript
## Splice Variants
In humans, LENG9 has two mRNA unspliced transcript variants.[5] Variant (1) is the longest and most conserved transcript of the gene and is made up of one exon that is composed of 1,919 bp.
# Protein
## General Properties
LENG9 is 501 amino acids in length, with a predicted molecular weight of 53.2 kDa.[10] The isoelectric point of LENG9 protein is predicted to be 7.7.[11] No known transmembrane sequences were found for LENG9.[12]
## Composition
Analysis of the LENG9 protein was performed against the "human" database,[10] which indicated a higher frequency of alanine and proline amino acids than of that of a normal human protein. Inversely, an abnormally lower frequency of aspartate, isoleucine, methionine, asparagine, serine, and tyrosine amino acids were detected.
## Structure
The secondary structure of LENG9 is predicted to be composed of alpha-helices and beta-sheets throughout the sequence.[14][13][15] The tertiary structure of LENG9 is displayed in the image to the right.
## Sub-cellular localization
A strong signal peptide detected in the mitochondrion region (0.788) suggests that the LENG9 protein localizes in the mitochondrial matrix.[12] However, further analysis among other mammal orthologs predicted sub-cellular localization in the cytoplasm and nuclear localization for Danio rerio.[12][16]
## Post Translational Modifications
LENG9 is predicted to undergo post-translational modifications such as phosphorylation, N-terminal acetylation, sumoylation, and C-terminal Glycosylphosphatidylinositol (GPI) anchor modification.
### Phosphorylation
LENG9 contains numerous phosphorylation sites distributed in the protein sequence, as show in the diagram to the right. These sites include casein kinase 2 (CK2), cAMP-dependent protein kinase (PKA), protein kinase C (PKC), ataxia-telangiectasia mutated kinase (ATM), cyclin-dependent kinase 5 (CDK5), and casein kinase 1 (CK1).[18]
### N-terminal Acetylation
There is one predicted N-terminal acetylation site found in the protein LENG9 at the serine amino acid position 3.[19]
### Sumoylation
There are two predicted sumoylation sites within LENG9 at position 82 and 452 on lysine residues.[20]
### C-Terminal GPI Anchor Modification
A C-terminal GPI modification site was found on the glycine residue at position 486.[21]
## Domains and Motifs
There are 3 conserved domains in LENG9. The metal-ion binding zinc finger domain ZnF_C3H1[22] is found from amino acid 46 to 61. LENG9 also has a domain of unknown function belonging to the domain family DUF504, that spans from amino acid 109 to 160. The last conserved domain spans from amino acid 320 to 500 and is known as AKAP7 2'5' RNA ligase-like domain (AKAP7_NLS).[5][23]
Conserved WD40 repeats are found in LENG9, spanning from amino acid 98 to 159.[13][24] This motif is characterized by beta-propeller structures in the tertiary structure.
## Protein Interactions
LENG9 is found to interact with the C9ORF41 protein that encodes methyltransferase, involved in converting carnosine to anserine present in skeletal muscle. Another interactor is CDC5L,[26] which is a positive regulator for the cell cycle for phase G2 to M transition.[27] FOXS1 is another interacting protein that functions as a transcriptional repressor to suppress promotors such as FASLG, FOXO3, and FOXO4.[28]
# Clinical Significance
## Disease Association
The LENG9 gene was found to be up-regulated and expressed in endothelial endometrium (hEECs) tissues during various stages of the menstrual/reproductive cycle when transfected with the RNA gene, miR-30d.[3][29] As ectopic over-expression of miR-30d in hEECs is observed to affect cancer-associated genes, LENG9 is predicted to play a role in reproductive and endocrine system disorders.
## Fertility
Analysis of endometrial receptivity using miRNA of receptive and prereceptive endometrium from fertile women also indicated significant up-regulation of miR-30d.[4] Consequently, the induced expression of LENG9 from miR-30d transfection suggests a possible relationship between the LENG9 gene and female fertility functions.
# Homology
## Evolution
Comparison of the LENG9 protein was conducted against fibrinogen and cytochrome C to observe the rate of evolutionary change. The relatively fast rate of change in LENG9 compared to that of other proteins suggests that the gene is adaptive for vital cell structures and functions.
## Paralogs
There are no known paralogs for LENG9.[2]
## Orthologs
LENG9 is highly conserved in mammals and bony fish such as the zebrafish.[24] It is also conserved a in few reptiles and amphibians.[31] The gene is not present in invertebrates, birds, bacteria, or fungi[32] | https://www.wikidoc.org/index.php/LENG9 | |
15f522ebba33aed423dde525491ef789900ee882 | wikidoc | LETM1 | LETM1
Leucine zipper-EF-hand containing transmembrane protein 1 is a protein that in humans is encoded by the LETM1 gene.
# Structure
The LETM1 protein has a transmembrane domain and a casein kinase 2 and protein kinase C phosphorylation site. The LETM1 gene is expressed in the mitochondria of many eukaryotes indicating that this is a conserved mitochondrial protein.
# Function
LETM1 is a eukaryotic protein that is expressed in the inner membrane of mitochondria. Experiments performed with human cells have been interpreted to indicate that it functions as a component of a Ca2+/H+ antiporter. Experimental results with yeast cells have been interpreted as suggesting that LETM1 functions as a component of a K+/H+ antiporter. The Drosophila melanogaster LETM1 protein has been shown to functionally substitute for the K+/H+ antiporter function in yeast cells.
# Clinical significance
Deletion of LETM1 is thought to be involved in the development of Wolf–Hirschhorn syndrome in humans. | LETM1
Leucine zipper-EF-hand containing transmembrane protein 1 is a protein that in humans is encoded by the LETM1 gene.[1]
# Structure
The LETM1 protein has a transmembrane domain and a casein kinase 2 and protein kinase C phosphorylation site.[2] The LETM1 gene is expressed in the mitochondria of many eukaryotes indicating that this is a conserved mitochondrial protein.[3]
# Function
LETM1 is a eukaryotic protein that is expressed in the inner membrane of mitochondria. Experiments performed with human cells have been interpreted to indicate that it functions as a component of a Ca2+/H+ antiporter.[4] Experimental results with yeast cells have been interpreted as suggesting that LETM1 functions as a component of a K+/H+ antiporter.[5] The Drosophila melanogaster LETM1 protein has been shown to functionally substitute for the K+/H+ antiporter function in yeast cells.[6]
# Clinical significance
Deletion of LETM1 is thought to be involved in the development of Wolf–Hirschhorn syndrome in humans.[2] | https://www.wikidoc.org/index.php/LETM1 | |
986aed99518d4aa9f8a9bed6d64357e2e2381886 | wikidoc | LIMK1 | LIMK1
LIM domain kinase 1 is an enzyme that in humans is encoded by the LIMK1 gene.
# Function
There are approximately 40 known eukaryotic LIM proteins, so named for the LIM domains they contain. LIM domains are highly conserved cysteine-rich structures containing 2 zinc fingers. Although zinc fingers usually function by binding to DNA or RNA, the LIM motif probably mediates protein-protein interactions. LIM kinase-1 and LIM kinase-2 belong to a small subfamily with a unique combination of 2 N-terminal LIM motifs, a central PDZ domain, and a C-terminal protein kinase domain. LIMK1 is likely to be a component of an intracellular signaling pathway and may be involved in brain development.
# Clinical significance
LIMK1 hemizygosity is implicated in the impaired visuospatial constructive cognition of Williams syndrome.
# Interactions
LIMK1 has been shown to interact with:
- CFL1,
- CDKN1C,
- NRG1,
- PAK1,
- PAK4, and
- YWHAZ. | LIMK1
LIM domain kinase 1 is an enzyme that in humans is encoded by the LIMK1 gene.[1][2]
# Function
There are approximately 40 known eukaryotic LIM proteins, so named for the LIM domains they contain. LIM domains are highly conserved cysteine-rich structures containing 2 zinc fingers. Although zinc fingers usually function by binding to DNA or RNA, the LIM motif probably mediates protein-protein interactions. LIM kinase-1 and LIM kinase-2 belong to a small subfamily with a unique combination of 2 N-terminal LIM motifs, a central PDZ domain, and a C-terminal protein kinase domain. LIMK1 is likely to be a component of an intracellular signaling pathway and may be involved in brain development.[3]
# Clinical significance
LIMK1 hemizygosity is implicated in the impaired visuospatial constructive cognition of Williams syndrome.[3]
# Interactions
LIMK1 has been shown to interact with:
- CFL1,[4][5]
- CDKN1C,[6]
- NRG1,[7]
- PAK1,[8]
- PAK4,[9] and
- YWHAZ.[10] | https://www.wikidoc.org/index.php/LIMK1 | |
359243b6fdb5a1d7fa012d58f7cdacc7ebaf7500 | wikidoc | LIMS1 | LIMS1
LIM and senescent cell antigen-like-containing domain protein 1 is a protein that in humans is encoded by the LIMS1 gene.
# Function
The protein encoded by this gene is an adaptor protein which contains five LIM domains, or double zinc fingers. The protein is likely involved in integrin signaling through its LIM domain-mediated interaction with integrin-linked kinase, found in focal adhesion plaques. It is also thought to act as a bridge linking integrin-linked kinase to NCK adaptor protein 2, which is involved in growth factor receptor kinase signaling pathways. Its localization to the periphery of spreading cells also suggests that this protein may play a role in integrin-mediated cell adhesion or spreading.
# Interactions
LIMS1 has been shown to interact with Integrin-linked kinase and NCK2. | LIMS1
LIM and senescent cell antigen-like-containing domain protein 1 is a protein that in humans is encoded by the LIMS1 gene.[1][2][3]
# Function
The protein encoded by this gene is an adaptor protein which contains five LIM domains, or double zinc fingers. The protein is likely involved in integrin signaling through its LIM domain-mediated interaction with integrin-linked kinase, found in focal adhesion plaques. It is also thought to act as a bridge linking integrin-linked kinase to NCK adaptor protein 2, which is involved in growth factor receptor kinase signaling pathways. Its localization to the periphery of spreading cells also suggests that this protein may play a role in integrin-mediated cell adhesion or spreading.[3]
# Interactions
LIMS1 has been shown to interact with Integrin-linked kinase[2][4] and NCK2.[2][5] | https://www.wikidoc.org/index.php/LIMS1 | |
8b561f532d6401a29018a77e6bd929513fdb340d | wikidoc | LIN28 | LIN28
Lin-28 homolog A is a protein that in humans is encoded by the LIN28 gene.
LIN28 encodes an RNA-binding protein that binds to and enhances the translation of the IGF-2 (insulin-like growth factor 2) mRNA. Lin28 binds to the let-7 pre-microRNA and blocks production of the mature let-7 microRNA in mouse embryonic stem cells. In pluripotent embryonal carcinoma cells, LIN28 is localized in the ribosomes, P-bodies and stress granules.
# Function
## Stem cell expression
LIN28 is thought to regulate the self-renewal of stem cells. In Caenorhabditis elegans, there is only one Lin28 gene that is expressed and in vertebrates, there are two paralogs present, Lin28a and Lin28b. In nematodes, the LIN28 homolog lin-28 is a heterochronic gene that determines the onset of early larval stages of developmental events in C. elegans, by regulating the self-renewal of nematode stem cells in the skin (called seam cells) and vulva (called VPCs) during development. In mice, LIN28 is highly expressed in mouse embryonic stem cells and during early embryogenesis.
LIN28 is highly expressed in human embryonic stem cells and can enhance the efficiency of the formation of induced pluripotent stem (iPS) cells from human fibroblasts.
## Puberty
LIN28 overexpression in mice can cause gigantism and a delay in puberty onset, consistent with human genome-wide association studies suggesting that polymorphisms in the human LIN28B gene are associated with human height and puberty timing. Mutations in LIN28B are associated with precocious puberty.
LIN28 can regulate glucose homeostasis in mammals by increasing insulin-PI3K-mTOR signaling and insulin sensitivity, thereby promoting resistance to high fat diet-induced obesity and type 2 diabetes. Aberrant expression of LIN28 has been seen to regulate aerobic glycolysis to facilitate cancer proliferation
## Tissue regeneration
Mice genetically altered to produce LIN28 during their lifespan showed improved hair growth. and healthy tissue regeneration on added puncture wounds in later life stages. While the mice could regenerate limbs, they could not repair damaged heart tissue. Appropriate drugs replicated the regeneration in unaltered mice, using the same metabolic paths. The drugs increased the subjects' metabolic rates, evidently causing the body to heal at higher rates. The effects of Lin28a activation faded with age.
# Structure
Models of Lin28/let-7 complexes obtained through X-ray crystallography and NMR reveal that two folded domains of Lin28 recognize two distinct RNA regions. The domains are sufficient for inhibition of let-7 in vivo.
# Applications
LIN28 is a marker of undifferentiated human embryonic stem cells and has been used to enhance the efficiency of the formation of iPS cells from human fibroblasts. | LIN28
Lin-28 homolog A is a protein that in humans is encoded by the LIN28 gene.[1][2]
LIN28 encodes an RNA-binding protein[3] that binds to and enhances the translation of the IGF-2 (insulin-like growth factor 2) mRNA.[4] Lin28 binds to the let-7 pre-microRNA and blocks production of the mature let-7 microRNA in mouse embryonic stem cells.[5][6] In pluripotent embryonal carcinoma cells, LIN28 is localized in the ribosomes, P-bodies and stress granules.[7]
# Function
## Stem cell expression
LIN28 is thought to regulate the self-renewal of stem cells. In Caenorhabditis elegans, there is only one Lin28 gene that is expressed and in vertebrates, there are two paralogs present, Lin28a and Lin28b. In nematodes, the LIN28 homolog lin-28 is a heterochronic gene that determines the onset of early larval stages of developmental events in C. elegans, by regulating the self-renewal of nematode stem cells in the skin (called seam cells) and vulva (called VPCs) during development.[8] In mice, LIN28 is highly expressed in mouse embryonic stem cells and during early embryogenesis.[9]
LIN28 is highly expressed in human embryonic stem cells[10] and can enhance the efficiency of the formation of induced pluripotent stem (iPS) cells from human fibroblasts.[11]
## Puberty
LIN28 overexpression in mice can cause gigantism and a delay in puberty onset, consistent with human genome-wide association studies suggesting that polymorphisms in the human LIN28B gene are associated with human height and puberty timing.[12] Mutations in LIN28B are associated with precocious puberty.[13]
LIN28 can regulate glucose homeostasis in mammals by increasing insulin-PI3K-mTOR signaling and insulin sensitivity, thereby promoting resistance to high fat diet-induced obesity and type 2 diabetes.[14] Aberrant expression of LIN28 has been seen to regulate aerobic glycolysis to facilitate cancer proliferation
## Tissue regeneration
Mice genetically altered to produce LIN28 during their lifespan showed improved hair growth.[15] and healthy tissue regeneration on added puncture wounds[15] in later life stages.[15] While the mice could regenerate limbs, they could not repair damaged heart tissue. Appropriate drugs replicated the regeneration in unaltered mice, using the same metabolic paths. The drugs increased the subjects' metabolic rates, evidently causing the body to heal at higher rates. The effects of Lin28a activation faded with age.[15][16]
# Structure
Models of Lin28/let-7 complexes obtained through X-ray crystallography and NMR reveal that two folded domains of Lin28 recognize two distinct RNA regions[17][18]. The domains are sufficient for inhibition of let-7 in vivo.[6][19]
# Applications
LIN28 is a marker of undifferentiated human embryonic stem cells[10] and has been used to enhance the efficiency of the formation of iPS cells from human fibroblasts.[11] | https://www.wikidoc.org/index.php/LIN28 | |
d42d77767ad00455ba3586aeb02da9369bd979d8 | wikidoc | LMAN1 | LMAN1
Protein ERGIC-53 also known as ER-Golgi intermediate compartment 53 kDa protein or lectin mannose-binding 1 is a protein that in humans is encoded by the LMAN1 gene.
# Function
ERGIC-53 (also named LMAN1) is a type I integral membrane protein localized in the intermediate region (ERGIC) between the endoplasmic reticulum and the Golgi, presumably recycling between the two compartments. The protein is a mannose-specific lectin and is a member of a novel family of plant lectin homologs in the secretory pathway of animal cells. Mutations in the gene are associated with a coagulation defect. Using positional cloning, the gene was identified as the disease gene leading to combined deficiency of factor V-factor VIII, a rare, autosomal recessive disorder in which both coagulation factors V and VIII are diminished. MCFD2 is the second gene that leads to combined deficiency of factor V-factor VIII. ERGIC-53 and MCFD2 form a protein complex and serve as a cargo receptor to transport FV and FVIII from the ER to the ERGIC and then the Golgi,as illustrated here.
# Clinical significance
LMAN1 mutational inactivation is a frequent and early event potentially contributing to colorectal tumorigenesis. | LMAN1
Protein ERGIC-53 also known as ER-Golgi intermediate compartment 53 kDa protein or lectin mannose-binding 1 is a protein that in humans is encoded by the LMAN1 gene.[1][2][3]
# Function
ERGIC-53 (also named LMAN1) is a type I integral membrane protein localized in the intermediate region (ERGIC) between the endoplasmic reticulum and the Golgi, presumably recycling between the two compartments. The protein is a mannose-specific lectin and is a member of a novel family of plant lectin homologs in the secretory pathway of animal cells. Mutations in the gene are associated with a coagulation defect. Using positional cloning, the gene was identified as the disease gene leading to combined deficiency of factor V-factor VIII, a rare, autosomal recessive disorder in which both coagulation factors V and VIII are diminished.[4][3] MCFD2 is the second gene that leads to combined deficiency of factor V-factor VIII.[5] ERGIC-53 and MCFD2 form a protein complex and serve as a cargo receptor to transport FV and FVIII from the ER to the ERGIC and then the Golgi,[6]as illustrated here.[4]
# Clinical significance
LMAN1 mutational inactivation is a frequent and early event potentially contributing to colorectal tumorigenesis.[7] | https://www.wikidoc.org/index.php/LMAN1 | |
39432280759f94cd5ae5b46623427d83941ee7d1 | wikidoc | LMTK2 | LMTK2
Serine/threonine-protein kinase LMTK2 also known as Lemur tyrosine kinase 2 (LMTK2) is an enzyme that in humans is encoded by the LMTK2 gene.
# Function
The LMTK2 enzyme belongs to both the protein kinase and the tyrosine kinase families. It contains N-terminus transmembrane helices and a long C-terminal cytoplasmic tail with serine/threonine/tyrosine kinase activity. This protein interacts with several other proteins, such as androgen receptor, inhibitor-2 (Inh2), protein phosphatase-1 (PP1C), p35, and myosin VI. It phosphorylates other proteins, and is itself also phosphorylated when interacting with cyclin-dependent kinase 5 (cdk5)/p35 complex. This protein is involved in nerve growth factor (NGF)-TrkA signalling, and also plays a critical role in endosomal membrane trafficking. Mouse studies suggested an essential role of this protein in spermatogenesis.
# Clinical significance
Loss of LMTK2 has been implicated to play a role in development of prostate cancer.
# Interactions
LMTK2 has been shown to interact with PPP1CA, Cyclin-dependent kinase 5 and PPP1R2. | LMTK2
Serine/threonine-protein kinase LMTK2 also known as Lemur tyrosine kinase 2 (LMTK2) is an enzyme that in humans is encoded by the LMTK2 gene.[1][2]
# Function
The LMTK2 enzyme belongs to both the protein kinase and the tyrosine kinase families. It contains N-terminus transmembrane helices and a long C-terminal cytoplasmic tail with serine/threonine/tyrosine kinase activity. This protein interacts with several other proteins, such as androgen receptor, inhibitor-2 (Inh2), protein phosphatase-1 (PP1C), p35, and myosin VI. It phosphorylates other proteins, and is itself also phosphorylated when interacting with cyclin-dependent kinase 5 (cdk5)/p35 complex. This protein is involved in nerve growth factor (NGF)-TrkA signalling, and also plays a critical role in endosomal membrane trafficking. Mouse studies suggested an essential role of this protein in spermatogenesis.[2]
# Clinical significance
Loss of LMTK2 has been implicated to play a role in development of prostate cancer.[3]
# Interactions
LMTK2 has been shown to interact with PPP1CA,[4] Cyclin-dependent kinase 5[5] and PPP1R2.[4] | https://www.wikidoc.org/index.php/LMTK2 | |
f4e56acffbf64358c9379e5127f599b0e2388c04 | wikidoc | LMX1B | LMX1B
LIM homeobox transcription factor 1-beta, also known as LMX1B, is a protein which in humans is encoded by the LMX1B gene.
# Function
LMX1B is a LIM homeobox transcription factor which plays a central role in dorso-ventral patterning of the vertebrate limb.
# Clinical significance
Mutations in the LMX1B gene are associated with the Nail-patella syndrome. | LMX1B
LIM homeobox transcription factor 1-beta, also known as LMX1B, is a protein which in humans is encoded by the LMX1B gene.[1][2]
# Function
LMX1B is a LIM homeobox transcription factor which plays a central role in dorso-ventral patterning of the vertebrate limb.[3]
# Clinical significance
Mutations in the LMX1B gene are associated with the Nail-patella syndrome.[4] | https://www.wikidoc.org/index.php/LMX1B | |
d91a983f0c7872105cf9f73c147ef258679abf15 | wikidoc | LONP1 | LONP1
Lon protease homolog, mitochondrial is an enzyme that in humans is encoded by the LONP1 gene.
# Structure
This gene encoded a mitochondrial matrix protein that is the subunit of a barrel-shaped homo-oligometric protein complex, the Lon protease. Lon protease is a member of ATP-dependent proteases (AAA+ proteases). Mature and catalytically viable Human Lon protease complex contains a hexameric ring while other formations of complexes have been observed (e.g., heptameric ring in Saccharomyces cerevisiae). A single subunit of Lon protease contains three domains, N-Domain for protein substrate recognition, AAA + module for ATP binding and hydrolysis, and P-domain for protein proteolysis. A similar protease expressed in E. coli regulates gene expression by targeting specific regulatory proteins for degradation. Lon protease binds a specific sequence in the light and heavy chain promoters of the mitochondrial genome which are involved in regulation of DNA replication and transcription.
# Function
Lon protease (LONP1) is a conserved serine peptidase identified from bacteria to eukaryotic cells. In mitochondrial matrix, a majority of damaged proteins is removed via proteolysis led by Lon protease, which is an essential mechanism for mitochondrial protein quality control (PQC).
For Lon protease-dependent degradation, protein substrates are first recognized and then unfolded if necessary in an ATP-dependent manner. The substrates are subsequently transferred through the pore of complex and into the proteolytic chamber of complex for degradation. ATP binding to the AAA module of the Lon complex results in a change in Lon conformation into a proteolytically active state. In general, Lon protease interacts with peptide regions(sequences) that are located within the hydrophobic core of substrates and rarely on the surface. These regions can be presented to Lon protease when proteins are damaged and lost their conformation integrity. In addition to misfolded proteins, several regulatory proteins can be processed by Lon protease by removing a degradable tag before they fully gain their biological functions.
LONP1 is also a DNA-binding protein that participates in mtDNA maintenance and gene expression regulation. LONP1 degrades mitochondrial transcription factor A (TFAM) when substrate is modified by post-translational modifications (PTMs) such as phosphorylation, regulating mtDNA copy number and metabolism to maintain the TFAM/mtDNA ratio necessary to control replication and transcription.
# Clinical significance
Given the crucial role of LON protease in maintaining the control of mitochondrial function, its dynamics in expression under stress conditions has been found associating with human diseases and aging. For example, LONP1 expression levels are increased in different tumors and tumor cell lines. Downregulation of LONP1 in some tumor cells causes apoptosis and cell death, indicating a possible addiction of tumor cells to LONP1 function, as occurs with other intracellular proteases associated with cancer. | LONP1
Lon protease homolog, mitochondrial is an enzyme that in humans is encoded by the LONP1 gene.[1][2][3][4]
# Structure
This gene encoded a mitochondrial matrix protein that is the subunit of a barrel-shaped homo-oligometric protein complex, the Lon protease. Lon protease is a member of ATP-dependent proteases (AAA+ proteases). Mature and catalytically viable Human Lon protease complex contains a hexameric ring while other formations of complexes have been observed (e.g., heptameric ring in Saccharomyces cerevisiae). A single subunit of Lon protease contains three domains, N-Domain for protein substrate recognition, AAA + module for ATP binding and hydrolysis, and P-domain for protein proteolysis. A similar protease expressed in E. coli regulates gene expression by targeting specific regulatory proteins for degradation. Lon protease binds a specific sequence in the light and heavy chain promoters of the mitochondrial genome which are involved in regulation of DNA replication and transcription.[3]
# Function
Lon protease (LONP1) is a conserved serine peptidase identified from bacteria to eukaryotic cells.[5] In mitochondrial matrix, a majority of damaged proteins is removed via proteolysis led by Lon protease, which is an essential mechanism for mitochondrial protein quality control (PQC).
For Lon protease-dependent degradation, protein substrates are first recognized and then unfolded if necessary in an ATP-dependent manner. The substrates are subsequently transferred through the pore of complex and into the proteolytic chamber of complex for degradation. ATP binding to the AAA module of the Lon complex results in a change in Lon conformation into a proteolytically active state. In general, Lon protease interacts with peptide regions(sequences) that are located within the hydrophobic core of substrates and rarely on the surface. These regions can be presented to Lon protease when proteins are damaged and lost their conformation integrity.[6] In addition to misfolded proteins, several regulatory proteins can be processed by Lon protease by removing a degradable tag before they fully gain their biological functions.[7]
LONP1 is also a DNA-binding protein that participates in mtDNA maintenance and gene expression regulation.[8] LONP1 degrades mitochondrial transcription factor A (TFAM) when substrate is modified by post-translational modifications (PTMs) such as phosphorylation, regulating mtDNA copy number and metabolism to maintain the TFAM/mtDNA ratio necessary to control replication and transcription.[9]
# Clinical significance
Given the crucial role of LON protease in maintaining the control of mitochondrial function,[10] its dynamics in expression under stress conditions has been found associating with human diseases and aging.[11][12] For example, LONP1 expression levels are increased in different tumors and tumor cell lines. Downregulation of LONP1 in some tumor cells causes apoptosis and cell death, indicating a possible addiction of tumor cells to LONP1 function, as occurs with other intracellular proteases associated with cancer. | https://www.wikidoc.org/index.php/LONP1 | |
6694adb482ba85cfc3c923582d6c9a1cd42745bc | wikidoc | LOXL1 | LOXL1
Lysyl oxidase homolog 1, also known as LOXL1, is an enzyme which in humans is encoded by the LOXL1 gene.
# Function
This gene encodes a member of the lysyl oxidase gene family. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyses the first step in the formation of crosslinks in collagens and elastin. A highly conserved amino acid sequence at the C-terminus end appears to be sufficient for amine oxidase activity, suggesting that each family member may retain this function. The N-terminus is poorly conserved and may impart additional roles in developmental regulation, senescence, tumor suppression, cell growth control, and chemotaxis to each member of the family.
# Clinical significance
Polymorphisms of the LOXL1 gene are associated with pseudoexfoliation syndrome, a disease where the extracellular matrix contains abnormal amounts of cross-linked, amyloid-like fibrillar material and glycoproteins. When this happens in the eye, exfoliation glaucoma results.
# Interactions
LOXL1 has been shown to interact with FBLN5. | LOXL1
Lysyl oxidase homolog 1, also known as LOXL1, is an enzyme which in humans is encoded by the LOXL1 gene.[1][2]
# Function
This gene encodes a member of the lysyl oxidase gene family. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyses the first step in the formation of crosslinks in collagens and elastin. A highly conserved amino acid sequence at the C-terminus end appears to be sufficient for amine oxidase activity, suggesting that each family member may retain this function. The N-terminus is poorly conserved and may impart additional roles in developmental regulation, senescence, tumor suppression, cell growth control, and chemotaxis to each member of the family.[1]
# Clinical significance
Polymorphisms of the LOXL1 gene are associated with pseudoexfoliation syndrome, a disease where the extracellular matrix contains abnormal amounts of cross-linked, amyloid-like fibrillar material and glycoproteins. When this happens in the eye, exfoliation glaucoma results.[3][4]
# Interactions
LOXL1 has been shown to interact with FBLN5.[5] | https://www.wikidoc.org/index.php/LOXL1 | |
dbba97d658609424533275623f1a0fd2dc6864ff | wikidoc | LOXL2 | LOXL2
Lysyl oxidase homolog 2 is an enzyme that in humans is encoded by the LOXL2 gene.
# Function
This gene encodes a member of the lysyl oxidase gene family. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyses the first step in the formation of crosslinks in collagens and elastin. A highly conserved amino acid sequence at the C-terminus end appears to be sufficient for amine oxidase activity, suggesting that each family member may retain this function. The N-terminus is poorly conserved and may impart additional roles in developmental regulation, senescence, tumor suppression, cell growth control, and chemotaxis to each member of the family.
LOXL2 can also crosslink collagen type IV and hence influence the sprouting of new blood vessels.
# Clinical significance
LOXL2 is an enzyme that is up-regulated in several types of cancer and is associated with a poorer prognosis. LOXL2 changes the structure of histones (proteins that are attached to DNA) and thus changes the shape of the cells, making it easier for the cancer cells to metastasize.
An antibody that inhibits the activity of LOXL2, simtuzumab and is currently in clinical trials for the treatment of several types of cancer and fibrotic diseases such as liver fibrosis. | LOXL2
Lysyl oxidase homolog 2 is an enzyme that in humans is encoded by the LOXL2 gene.[1][2]
# Function
This gene encodes a member of the lysyl oxidase gene family. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyses the first step in the formation of crosslinks in collagens and elastin. A highly conserved amino acid sequence at the C-terminus end appears to be sufficient for amine oxidase activity, suggesting that each family member may retain this function. The N-terminus is poorly conserved and may impart additional roles in developmental regulation, senescence, tumor suppression, cell growth control, and chemotaxis to each member of the family.[2]
LOXL2 can also crosslink collagen type IV and hence influence the sprouting of new blood vessels.[3]
# Clinical significance
LOXL2 is an enzyme that is up-regulated in several types of cancer and is associated with a poorer prognosis.[4][5] LOXL2 changes the structure of histones (proteins that are attached to DNA)[6] and thus changes the shape of the cells, making it easier for the cancer cells to metastasize.[7]
An antibody that inhibits the activity of LOXL2, simtuzumab and is currently in clinical trials for the treatment of several types of cancer and fibrotic diseases such as liver fibrosis.[8] | https://www.wikidoc.org/index.php/LOXL2 |
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