WordNet

any of various controls or devices for regulating or controlling fluid flow, pressure, temperature, etc.
an official responsible for control and supervision of a particular activity or area of public interest
a materials capacity to conduct electricity; measured as the reciprocal of electrical resistance
of or relating to or resembling a cyst
of or relating to a normal cyst (as the gallbladder or urinary bladder)
development of excess fibrous connective tissue in an organ
a closed sac that develops abnormally in some body structure

PrepTutorEJDIC

取り締まり人;調整者 / 調整装置
(熱・電気などの)伝導度
胞嚢(ほうのう)性の
線維症(線維性結合線維が増殖し過ぎる症状)
胞嚢(ほうのう)

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/06 08:47:02」(JST)

wiki en

Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and chloride channel in vertebrates that is encoded by the CFTR gene.^[1]^[2]

CFTR is an ABC transporter-class ion channel that codes for a protein that conducts chloride^[3] and thiocyanate^[4] ions across epithelial cell membranes. Mutations of the CFTR gene affecting chloride ion channel function lead to dysregulation of epithelial fluid transport in the lung, pancreas and other organs, resulting in cystic fibrosis. Complications include thickened mucus in the lungs with frequent respiratory infections, and pancreatic insufficiency giving rise to malnutrition and diabetes. These conditions lead to chronic disability and reduced life expectancy. In male patients, the progressive obstruction and destruction of the developing vas deferens and epididymis appear to result from abnormal intraluminal secretions,^[5] causing congenital absence of the vas deferens and male infertility.

Gene

The location of the CFTR gene on chromosome 7

The gene that encodes the human CFTR protein is found on chromosome 7, on the long arm at position q31.2.^[2] from base pair 116,907,253 to base pair 117,095,955. CFTR orthologs ^[6] occur in the jawed vertebrates.^[7]

The CFTR gene has been used in animals as a nuclear DNA phylogenetic marker.^[6] Large genomic sequences of this gene have been used to explore the phylogeny of the major groups of mammals,^[8] and confirmed the grouping of placental orders into four major clades: Xenarthra, Afrotheria, Laurasiatheria, and Euarchonta plus Glires.

Mutations

Nearly two thousand cystic fibrosis-causing mutations have been described.^[9] The most common mutation, ΔF508 results from a deletion (Δ) of three nucleotides which results in a loss of the amino acid phenylalanine (F) at the 508th position on the protein. As a result the protein does not fold normally and is more quickly degraded. The vast majority of mutations are infrequent. The distribution and frequency of mutations varies among different populations which has implications for genetic screening and counseling.

Mutations consist of replacements, duplications, deletions or shortenings in the CFTR gene. This may result in proteins that may not function, work less effectively, are more quickly degraded, or are present in inadequate numbers.^[10]

It has been hypothesized that mutations in the CFTR gene may confer a selective advantage to heterozygous individuals. Cells expressing a mutant form of the CFTR protein are resistant to invasion by the Salmonella typhi bacterium, the agent of typhoid fever, and mice carrying a single copy of mutant CFTR are resistant to diarrhea caused by cholera toxin.^[11]

List of common mutations

The most common mutations among caucasians are:^[12]

ΔF508
G542X
G551D
N1303K
W1282X

Structure

The CFTR gene is approximately 189 kb in length, with 27 exons and 26 introns.^[13] CFTR is a glycoprotein with 1480 amino acids. The protein consists of five domains. There are two transmembrane domains, each with six spans of alpha helices. These are each connected to a nucleotide binding domain (NBD) in the cytoplasm. The first NBD is connected to the second transmembrane domain by a regulatory "R" domain that is a unique feature of CFTR, not present in other ABC transporters. The ion channel only opens when its R-domain has been phosphorylated by PKA and ATP is bound at the NBDs.^[14] The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ-interacting domain.^[15]

Location and function

The CFTR protein is a channel protein that controls the flow of H₂O and Cl⁻ ions in and out of cells inside the lungs. When the CFTR protein is working correctly, as shown in Panel 1, ions freely flow in and out of the cells. However, when the CFTR protein is malfunctioning as in Panel 2, these ions cannot flow out of the cell due to a blocked channel. This causes cystic fibrosis, characterized by the buildup of thick mucus in the lungs.

CFTR functions as an ATP-gated anion channel, increasing the conductance for certain anions (e.g. Cl⁻) to flow down their electrochemical gradient. ATP-driven conformational changes in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient.^[1] This in contrast to other ABC proteins, in which ATP-driven conformational changes fuel uphill substrate transport across cellular membranes. Essentially, CFTR is an ion channel that evolved as a 'broken' ABC transporter that leaks when in open conformation.

The CFTR is found in the epithelial cells of many organs including the lung, liver, pancreas, digestive tract, reproductive tract, and skin. Normally, the protein moves chloride and thiocyanate^[16] ions (with a negative charge) out of an epithelial cell to the covering mucus. Positively charged sodium ions follow passively, increasing the total electrolyte concentration in the mucus, resulting in the movement of water out of cell by osmosis.

In epithelial cells with motile cilia lining the bronchus and the oviduct, CFTR is located on cell membrane but not on cilia. In contrast to CFTR, ENaC is located along the entire length of the cilia.^[17] These findings contradict a previous hypothesis that CFTR normally downregulates ENaC by direct interaction and that in CF patients, CFTR cannot downregulate ENaC causing hyper-absorption in the lungs and recurrent lung infections.

In sweat glands, CFTR defects result in reduced transport of sodium chloride and sodium thiocyanate^[18] in the reabsorptive duct and saltier sweat. This was the basis of a clinically important sweat test for cystic fibrosis before genetic screening was available.^[19]

Interactions

Cystic fibrosis transmembrane conductance regulator has been shown to interact with:

DNAJC5,^[20]
GOPC,^[21]^[22]^[22]
PDZK1,^[22]^[23]
PRKCE,^[24]
SLC4A8,^[25]
SNAP23,^[26]
SLC9A3R1,^[15]^[25]^[27]^[28]^[29]^[30]
SLC9A3R2,^[31] and
STX1A,^[26]^[32]

It is inhibited by the anti-diarrhoea drug crofelemer.

Related conditions

Congenital bilateral absence of vas deferens: Males with congenital bilateral absence of the vas deferens most often have a mild mutation (a change that allows partial function of the gene) in one copy of the CFTR gene and a cystic fibrosis-causing mutation in the other copy of CFTR.

Cystic fibrosis: More than 1,800 mutations in the CFTR gene have been found^[33] but the majority of these have not been associated with cystic fibrosis.^{[citation needed]} Most of these mutations either substitute one amino acid (a building block of proteins) for another amino acid in the CFTR protein or delete a small amount of DNA in the CFTR gene. The most common mutation, called ΔF508, is a deletion (Δ) of one amino acid (phenylalanine) at position 508 in the CFTR protein. This altered protein never reaches the cell membrane because it is degraded shortly after it is made. All disease-causing mutations in the CFTR gene prevent the channel from functioning properly, leading to a blockage of the movement of salt and water into and out of cells. As a result of this blockage, cells that line the passageways of the lungs, pancreas, and other organs produce abnormally thick, sticky mucus. This mucus obstructs the airways and glands, causing the characteristic signs and symptoms of cystic fibrosis. In addition, only thin mucus can be removed by cilia; thick mucus cannot, so it traps bacteria that give rise to chronic infections.

Cholera: The CFTR channel is up-regulated by cholera toxin-mediated ADP-ribosylation, resulting in increased production of cAMP, which leads to oversecretion of Cl⁻. Na⁺ and H₂O follow Cl⁻ into the small intestine, resulting in dehydration and loss of electrolytes.^{[citation needed]}

References

^ ^a ^b Gadsby DC, Vergani P, Csanády L (2006). "The ABC protein turned chloride channel whose failure causes cystic fibrosis". Nature 440 (7083): 477–83. Bibcode:2006Natur.440..477G. doi:10.1038/nature04712. PMC 2720541. PMID 16554808.
^ ^a ^b Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N (September 1989). "Identification of the cystic fibrosis gene: chromosome walking and jumping". Science 245 (4922): 1059–65. Bibcode:1989Sci...245.1059R. doi:10.1126/science.2772657. PMID 2772657.
^ Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL (1989). "Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA". Science 245 (4922): 1066–73. Bibcode:1989Sci...245.1066R. doi:10.1126/science.2475911. PMID 2475911.
^ Childers M, Eckel G, Himmel A, Caldwell J (2007). "A new model of cystic fibrosis pathology: lack of transport of glutathione and its thiocyanate conjugates". Med. Hypotheses 68 (1): 101–12. doi:10.1016/j.mehy.2006.06.020. PMID 16934416.
^ Marcorelles P, Gillet D, Friocourt G, Ledé F, Samaison L, Huguen G, Ferec C (March 2012). "Cystic fibrosis transmembrane conductance regulator protein expression in the male excretory duct system during development". Hum. Pathol. 43 (3): 390–7. doi:10.1016/j.humpath.2011.04.031. PMID 21840567.
^ ^a ^b "OrthoMaM phylogenetic marker: CFTR coding sequence".
^ Davies, R; Conroy, S-J; Davies, WL; Potter, IC; Rrezise, Ann EO (19–23 June 2005). "Evolution and Regulation of the Cystic Fibrosis Gene" (conference paper). Molecular Biology and Evolution (MBE05) Conference. Retrieved 28 July 2014.
^ Prasad AB, Allard MW, Green ED (2008). "Confirming the phylogeny of mammals by use of large comparative sequence data sets". Mol. Biol. Evol. 25 (9): 1795–808. doi:10.1093/molbev/msn104. PMC 2515873. PMID 18453548.
^ "Cystic Fibrosis Mutation Database: Statistics". Cystic Fibrosis Centre at the Hospital for Sick Children in Toronto. Retrieved 28 July 2014.
^ Rowe SM, Miller S, Sorscher EJ (May 2005). "Cystic fibrosis". N. Engl. J. Med. 352 (19): 1992–2001. doi:10.1056/NEJMra043184. PMID 15888700.
^ Kavic SM, Frehm EJ, Segal AS (1999). "Case studies in cholera: lessons in medical history and science". Yale J Biol Med 72 (6): 393–408. PMC 2579035. PMID 11138935.
^ Araújo FG, Novaes FC, Santos NP, Martins VC, Souza SM, Santos SE, Ribeiro-dos-Santos AK (January 2005). "Prevalence of deltaF508, G551D, G542X, and R553X mutations among cystic fibrosis patients in the North of Brazil". Braz. J. Med. Biol. Res. 38 (1): 11–5. doi:10.1590/S0100-879X2005000100003. PMID 15665983.
^ Cystic Fibrosis Mutation Database. "Genomic DNA sequence".
^ Sheppard DN, Welsh MJ (January 1999). "Structure and function of the CFTR chloride channel". Physiol. Rev. 79 (1 Suppl): S23–45. PMID 9922375.
^ ^a ^b Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ, Milgram SL (July 1998). "An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton". J. Biol. Chem. 273 (31): 19797–801. doi:10.1074/jbc.273.31.19797. PMID 9677412.
^ Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, Bánfi B (January 2007). "A novel host defense system of airways is defective in cystic fibrosis". Am. J. Respir. Crit. Care Med. 175 (2): 174–83. doi:10.1164/rccm.200607-1029OC. PMC 2720149. PMID 17082494.
^ Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A (2012). "Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways". Histochem. Cell Biol. 137 (3): 339–53. doi:10.1007/s00418-011-0904-1. PMID 22207244.
^ Xu Y, Szép S, Lu Z (2009). "The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases". Proc. Natl. Acad. Sci. U.S.A. 106 (48): 20515–9. Bibcode:2009PNAS..10620515X. doi:10.1073/pnas.0911412106. PMC 2777967. PMID 19918082.
^ Yonei Y, Tanaka M, Ozawa Y, Miyazaki K, Tsukada N, Inada S, Inagaki Y, Miyamoto K, Suzuki O, Okawa H (April 1992). "Primary hepatocellular carcinoma with severe hypoglycemia: involvement of insulin-like growth factors". Liver 12 (2): 90–3. doi:10.1111/j.1600-0676.1992.tb00563.x. PMID 1320177.
^ Zhang H, Peters KW, Sun F, Marino CR, Lang J, Burgoyne RD, Frizzell RA (2002). "Cysteine string protein interacts with and modulates the maturation of the cystic fibrosis transmembrane conductance regulator". J. Biol. Chem. 277 (32): 28948–58. doi:10.1074/jbc.M111706200. PMID 12039948.
^ Cheng J, Moyer BD, Milewski M, Loffing J, Ikeda M, Mickle JE, Cutting GR, Li M, Stanton BA, Guggino WB (2002). "A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression". J. Biol. Chem. 277 (5): 3520–9. doi:10.1074/jbc.M110177200. PMID 11707463.
^ ^a ^b ^c Gentzsch M, Cui L, Mengos A, Chang XB, Chen JH, Riordan JR (2003). "The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins". J. Biol. Chem. 278 (8): 6440–9. doi:10.1074/jbc.M211050200. PMID 12471024.
^ Wang S, Yue H, Derin RB, Guggino WB, Li M (2000). "Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity". Cell 103 (1): 169–79. doi:10.1016/S0092-8674(00)00096-9. PMID 11051556.
^ Liedtke CM, Yun CH, Kyle N, Wang D (2002). "Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor". J. Biol. Chem. 277 (25): 22925–33. doi:10.1074/jbc.M201917200. PMID 11956211.
^ ^a ^b Park M, Ko SB, Choi JY, Muallem G, Thomas PJ, Pushkin A, Lee MS, Kim JY, Lee MG, Muallem S, Kurtz I (2002). "The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3". J. Biol. Chem. 277 (52): 50503–9. doi:10.1074/jbc.M201862200. PMID 12403779.
^ ^a ^b Cormet-Boyaka E, Di A, Chang SY, Naren AP, Tousson A, Nelson DJ, Kirk KL (2002). "CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex". Proc. Natl. Acad. Sci. U.S.A. 99 (19): 12477–82. Bibcode:2002PNAS...9912477C. doi:10.1073/pnas.192203899. PMC 129470. PMID 12209004.
^ Hegedüs T, Sessler T, Scott R, Thelin W, Bakos E, Váradi A, Szabó K, Homolya L, Milgram SL, Sarkadi B (2003). "C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins". Biochem. Biophys. Res. Commun. 302 (3): 454–61. doi:10.1016/S0006-291X(03)00196-7. PMID 12615054.
^ Wang S, Raab RW, Schatz PJ, Guggino WB, Li M (1998). "Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)". FEBS Lett. 427 (1): 103–8. doi:10.1016/S0014-5793(98)00402-5. PMID 9613608.
^ Moyer BD, Duhaime M, Shaw C, Denton J, Reynolds D, Karlson KH, Pfeiffer J, Wang S, Mickle JE, Milewski M, Cutting GR, Guggino WB, Li M, Stanton BA (2000). "The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane". J. Biol. Chem. 275 (35): 27069–74. doi:10.1074/jbc.M004951200. PMID 10852925.
^ Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ (1998). "A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins". Proc. Natl. Acad. Sci. U.S.A. 95 (15): 8496–501. Bibcode:1998PNAS...95.8496H. doi:10.1073/pnas.95.15.8496. PMC 21104. PMID 9671706.
^ Sun F, Hug MJ, Lewarchik CM, Yun CH, Bradbury NA, Frizzell RA (2000). "E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells". J. Biol. Chem. 275 (38): 29539–46. doi:10.1074/jbc.M004961200. PMID 10893422.
^ Naren AP, Nelson DJ, Xie W, Jovov B, Pevsner J, Bennett MK, Benos DJ, Quick MW, Kirk KL (1997). "Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms". Nature 390 (6657): 302–5. Bibcode:1997Natur.390..302N. doi:10.1038/36882. PMID 9384384.
^ The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org , accessed 2013-12-12

External links

GeneReviews/NCBI/NIH/UW entry on CFTR-Related Disorders - Cystic Fibrosis (CF, Mucoviscidosis) and Congenital Absence of the Vas Deferens (CAVD)
The Cystic Fibrosis Transmembrane Conductance Regulator Protein
The Human Gene Mutation Database - CFTR Records
Cystic Fibrosis Mutation Database
Oak Ridge National Laboratory CFTR Information
CFTR at OMIM (National Center for Biotechnology Information)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 嚢胞性線維症：遺伝学と病因 cystic fibrosis genetics and pathogenesis
2. 嚢胞性線維症：臨床症状および診断 cystic fibrosis clinical manifestations and diagnosis
3. 嚢胞性線維症：肺疾患治療の概要 cystic fibrosis overview of the treatment of lung disease
4. 嚢胞性線維症：肝胆道系疾患 cystic fibrosis hepatobiliary disease
5. 嚢胞性線維症：実験的治療 cystic fibrosis investigational therapies

English Journal

Spectrum and distribution of CFTR gene mutations in asthma and chronic pancreatitis cases of North Indian population.

Muthuswamy S1, Agarwal S2, Awasthi S3, Singh S1, Dixit P3, Maurya N3, Choudhuri G4.Author information 1Deptarment of Medical Genetics, SGPGIMS, Lucknow 226014, India.2Deptarment of Medical Genetics, SGPGIMS, Lucknow 226014, India. Electronic address: saritasgpgi@gmail.com.3Department of Pediatrics, KGMU, Lucknow 226003, India.4Institute of Digestive and Hepatobiliary Sciences, Medanta Medcity, New Delhi, India.AbstractBACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) gene accounts for an autosomal recessive condition called cystic fibrosis (CF). In the Indian subcontinent, CF and its related diseases are under-diagnosed by the medical community due to poor knowledge of the disease and its confounding diagnosis, and also due to poor medical facilities available for these patients, thus causing an increased infant mortality rate with a low life expectancy in general. The aim of the study was to document the spectrum and distribution of CFTR mutations in controls, asthma and chronic pancreatitis cases of North India.
Gene.Gene.2014 Apr 10;539(1):125-31. doi: 10.1016/j.gene.2014.01.022. Epub 2014 Jan 14.
BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) gene accounts for an autosomal recessive condition called cystic fibrosis (CF). In the Indian subcontinent, CF and its related diseases are under-diagnosed by the medical community due to poor knowledge of the disease and its con
PMID 24440239

Antimicrobial responses of teleost phagocytes and innate immune evasion strategies of intracellular bacteria.

Grayfer L1, Hodgkinson JW2, Belosevic M3.Author information 1Department of Microbiology and Immunology, University of Rochester, Rochester, NY, USA.2Department of Biological Sciences, University of Alberta, Edmonton, Canada.3Department of Biological Sciences, University of Alberta, Edmonton, Canada; School of Public Health, University of Alberta, Edmonton, Canada. Electronic address: mike.belosevic@ualberta.ca.AbstractDuring infection, macrophage lineage cells eliminate infiltrating pathogens through a battery of antimicrobial responses, where the efficacy of these innate immune responses is pivotal to immunological outcomes. Not surprisingly, many intracellular pathogens have evolved mechanisms to overcome macrophage defenses, using these immune cells as residences and dissemination strategies. With pathogenic infections causing increasing detriments to both aquacultural and wild fish populations, it is imperative to garner greater understanding of fish phagocyte antimicrobial responses and the mechanisms by which aquatic pathogens are able to overcome these teleost macrophage barriers. Insights into the regulation of macrophage immunity of bony fish species will lend to the development of more effective aquacultural prophylaxis as well as broadening our understanding of the evolution of these immune processes. Accordingly, this review focuses on recent advances in the understanding of teleost macrophage antimicrobial responses and the strategies by which intracellular fish pathogens are able to avoid being killed by phagocytes, with a focus on Mycobacterium marinum.
Developmental and comparative immunology.Dev Comp Immunol.2014 Apr;43(2):223-42. doi: 10.1016/j.dci.2013.08.003. Epub 2013 Aug 15.
During infection, macrophage lineage cells eliminate infiltrating pathogens through a battery of antimicrobial responses, where the efficacy of these innate immune responses is pivotal to immunological outcomes. Not surprisingly, many intracellular pathogens have evolved mechanisms to overcome macro
PMID 23954721

Knockout mice reveal key roles for claudin 18 in alveolar barrier properties and fluid homeostasis.

Li G1, Flodby P, Luo J, Kage H, Sipos A, Gao D, Ji Y, Beard LL, Marconett CN, Demaio L, Kim YH, Kim KJ, Laird-Offringa IA, Minoo P, Liebler JM, Zhou B, Crandall ED, Borok Z.Author information 1USC, Medicine, Los Angeles, California, United States ; guanglei.li@gmail.com.AbstractClaudin proteins are major constituents of epithelial and endothelial tight junctions (TJ) that regulate paracellular permeability to ions and solutes. Claudin 18, a member of the large claudin family, is highly expressed in lung alveolar epithelium. To elucidate the role of claudin 18 in alveolar epithelial barrier function, we generated claudin 18 knockout (C18 KO) mice. C18 KO mice exhibited increased solute permeability and alveolar fluid clearance (AFC) compared to wild type (WT) controls. Increased AFC in C18 KO mice was associated with increased β-adrenergic receptor signaling together with activation of cystic fibrosis transmembrane conductance regulator (CFTR), higher epithelial sodium channel (ENaC) and Na-K-ATPase (Na pump) activity and increased Na-K-ATPase β1 subunit expression. Consistent with in vivo findings, C18 KO alveolar epithelial cell (AEC) monolayers exhibited lower transepithelial electrical resistance (RT) and increased solute and ion permeability with unchanged ion selectivity. Claudin 3 and claudin 4 expression was markedly increased, while claudin 5 was unchanged and occludin significantly decreased, in C18 KO mice. Microarray analysis revealed changes in cytoskeleton-associated gene expression in C18 KO mice, consistent with observed F-actin cytoskeletal rearrangement in AEC monolayers. These findings demonstrate a crucial non-redundant role for claudin 18 in regulation of alveolar epithelial TJ composition and permeability properties. Importantly, increased AFC in C18 KO mice identifies a role for claudin 18 in alveolar fluid homeostasis beyond its direct contributions to barrier properties that may at least in part serve to compensate for increased permeability.
American journal of respiratory cell and molecular biology.Am J Respir Cell Mol Biol.2014 Mar 3. [Epub ahead of print]
Claudin proteins are major constituents of epithelial and endothelial tight junctions (TJ) that regulate paracellular permeability to ions and solutes. Claudin 18, a member of the large claudin family, is highly expressed in lung alveolar epithelium. To elucidate the role of claudin 18 in alveolar e
PMID 24588076

Japanese Journal

のう胞性線維症におけるトランスレーショナルリサーチ

吉村邦彦,江島美保
呼吸器内科 21(6), 565-574, 2012-06
NAID 40019361476

Novel Action of the Chalcone Isoliquiritigenin as a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibitor : Potential Therapy for Cholera and Polycystic Kidney Disease

MUANPRASAT Chatchai,SIRIANANT Lalida,SOODVILAI Sunhapas,CHOKCHAISIRI Ratchanaporn,SUKSAMRARN Apichart,CHATSUDTHIPONG Varanuj
Journal of pharmacological sciences 118(1), 82-91, 2012-01-20
NAID 10030454282

「嚢胞性線維症膜貫通調節蛋白質」

Cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)
	NBD1 of human CFTR complexed with ATP. PDB rendering based on 1xmi.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1NBD, 1XMI, 1XMJ, 2BBO, 2BBS, 2BBT, 2LOB, 2PZE, 2PZF, 2PZG, 3GD7, 3ISW
Identifiers
Symbols	CFTR ; ABC35; ABCC7; CF; CFTR/MRP; MRP7; TNR-CFTR; dJ760C5.1
External IDs	OMIM: 602421 HomoloGene: 55465 IUPHAR: 707 ChEMBL: 4051 GeneCards: CFTR Gene
EC number	3.6.3.49
Gene ontology
Molecular function	• ATP-binding and phosphorylation-dependent chloride channel activity; • chloride channel activity; • channel-conductance-controlling ATPase activity; • protein binding; • ATP binding; • bicarbonate transmembrane transporter activity; • chloride transmembrane transporter activity; • chloride channel inhibitor activity; • enzyme binding; • PDZ domain binding;
Cellular component	• cytoplasm; • lysosomal membrane; • early endosome; • cytosol; • plasma membrane; • cell surface; • basolateral plasma membrane; • apical plasma membrane; • Golgi-associated vesicle membrane; • endoplasmic reticulum Sec complex; • early endosome membrane; • chloride channel complex; • protein complex; • recycling endosome; • extracellular exosome;
Biological process	• cholesterol biosynthetic process; • transport; • small GTPase mediated signal transduction; • respiratory gaseous exchange; • bicarbonate transport; • cholesterol transport; • positive regulation of insulin secretion involved in cellular response to glucose stimulus; • positive regulation of exocytosis; • sperm capacitation; • intracellular pH elevation; • transmembrane transport; • membrane hyperpolarization; • cellular response to cAMP; • positive regulation of cyclic nucleotide-gated ion channel activity; • chloride transmembrane transport; • positive regulation of voltage-gated chloride channel activity;
	Sources: Amigo / QuickGO
Orthologs
	v; t; e;

　　[★]

英: cystic fibrosis transmembrane regulator, cystic fibrosis transmembrane conductance regulator, CFTR
同: 嚢胞性線維性膜貫通調節因子？
関: 塩素イオンチャネル、クロライドチャネル; 胞性線維症膜貫通調節蛋白質？

Cl-分泌を行う上皮に広く発現
2つのヌクレオチド結合ドメイン(NBD)を有している。 (SP.42)
ABCトランスポーターというスーパーファミリーに属している。 (SP.42)
2つの作用がある

1. PKAでリン酸化されると活性化され、NBDでのATP加水分解によって開口するCl-チャネル。 (SP.42)
2. cAMP感受性Cl-チャネルを制御 (SP.707)

CFTRがないとCl-チャネルが機能しない→細胞内cAMPが上がってもCl-イオンが分泌されない (SP.707)
コレラなどにより細胞内cAMP濃度が上昇しても脱水を免れる (SP.707)

「CFTR gene」

　　[★]

同: cystic fibrosis transmembrane conductance regulator

「conductance」

　　[★]

n.

コンダクタンス、透過性

関: permeability、permeabilize、permeable

「transmembrane」

　　[★]

膜貫通の、膜貫通型の

関: membrane-spanning、TM、transmembranous

「regulator」

　　[★]

n.

制御因子、レギュレーター

関: regulatory factor

「transmembrane conductance」

　　[★]

膜コンダクタンス

関: membrane conductance

「cystic」

　　[★]

adj.

嚢胞性の

[The_ABC_protein_turned_chloride_channel_whose_failure_causes_cystic_fibrosis-1] Gadsby DC, Vergani P, Csanády L (2006). "The ABC protein turned chloride channel whose failure causes cystic fibrosis". Nature 440 (7083): 477–83. Bibcode:2006Natur.440..477G. doi:10.1038/nature04712. PMC 2720541. PMID 16554808.

[pmid2772657-2] Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N (September 1989). "Identification of the cystic fibrosis gene: chromosome walking and jumping". Science 245 (4922): 1059–65. Bibcode:1989Sci...245.1059R. doi:10.1126/science.2772657. PMID 2772657.

[pmid2475911-3] Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL (1989). "Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA". Science 245 (4922): 1066–73. Bibcode:1989Sci...245.1066R. doi:10.1126/science.2475911. PMID 2475911.

[pmid16934416-4] Childers M, Eckel G, Himmel A, Caldwell J (2007). "A new model of cystic fibrosis pathology: lack of transport of glutathione and its thiocyanate conjugates". Med. Hypotheses 68 (1): 101–12. doi:10.1016/j.mehy.2006.06.020. PMID 16934416.

[5] Marcorelles P, Gillet D, Friocourt G, Ledé F, Samaison L, Huguen G, Ferec C (March 2012). "Cystic fibrosis transmembrane conductance regulator protein expression in the male excretory duct system during development". Hum. Pathol. 43 (3): 390–7. doi:10.1016/j.humpath.2011.04.031. PMID 21840567.

[OrthoMaM-6] "OrthoMaM phylogenetic marker: CFTR coding sequence".

[7] Davies, R; Conroy, S-J; Davies, WL; Potter, IC; Rrezise, Ann EO (19–23 June 2005). "Evolution and Regulation of the Cystic Fibrosis Gene" (conference paper). Molecular Biology and Evolution (MBE05) Conference. Retrieved 28 July 2014.

[pmid18453548-8] Prasad AB, Allard MW, Green ED (2008). "Confirming the phylogeny of mammals by use of large comparative sequence data sets". Mol. Biol. Evol. 25 (9): 1795–808. doi:10.1093/molbev/msn104. PMC 2515873. PMID 18453548.

[url_genet.sickkids.on.ca-9] "Cystic Fibrosis Mutation Database: Statistics". Cystic Fibrosis Centre at the Hospital for Sick Children in Toronto. Retrieved 28 July 2014.

[pmid15888700-10] Rowe SM, Miller S, Sorscher EJ (May 2005). "Cystic fibrosis". N. Engl. J. Med. 352 (19): 1992–2001. doi:10.1056/NEJMra043184. PMID 15888700.

[11] Kavic SM, Frehm EJ, Segal AS (1999). "Case studies in cholera: lessons in medical history and science". Yale J Biol Med 72 (6): 393–408. PMC 2579035. PMID 11138935.

[mutations-12] Araújo FG, Novaes FC, Santos NP, Martins VC, Souza SM, Santos SE, Ribeiro-dos-Santos AK (January 2005). "Prevalence of deltaF508, G551D, G542X, and R553X mutations among cystic fibrosis patients in the North of Brazil". Braz. J. Med. Biol. Res. 38 (1): 11–5. doi:10.1590/S0100-879X2005000100003. PMID 15665983.

[CFMD-13] Cystic Fibrosis Mutation Database. "Genomic DNA sequence".

[pmid9922375-14] Sheppard DN, Welsh MJ (January 1999). "Structure and function of the CFTR chloride channel". Physiol. Rev. 79 (1 Suppl): S23–45. PMID 9922375.

[pmid9677412-15] Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ, Milgram SL (July 1998). "An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton". J. Biol. Chem. 273 (31): 19797–801. doi:10.1074/jbc.273.31.19797. PMID 9677412.

[pmid17082494-16] Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, Bánfi B (January 2007). "A novel host defense system of airways is defective in cystic fibrosis". Am. J. Respir. Crit. Care Med. 175 (2): 174–83. doi:10.1164/rccm.200607-1029OC. PMC 2720149. PMID 17082494.

[pmid22207244-17] Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A (2012). "Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways". Histochem. Cell Biol. 137 (3): 339–53. doi:10.1007/s00418-011-0904-1. PMID 22207244.

[pmid19918082-18] Xu Y, Szép S, Lu Z (2009). "The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases". Proc. Natl. Acad. Sci. U.S.A. 106 (48): 20515–9. Bibcode:2009PNAS..10620515X. doi:10.1073/pnas.0911412106. PMC 2777967. PMID 19918082.

[pmid1320177-19] Yonei Y, Tanaka M, Ozawa Y, Miyazaki K, Tsukada N, Inada S, Inagaki Y, Miyamoto K, Suzuki O, Okawa H (April 1992). "Primary hepatocellular carcinoma with severe hypoglycemia: involvement of insulin-like growth factors". Liver 12 (2): 90–3. doi:10.1111/j.1600-0676.1992.tb00563.x. PMID 1320177.

[pmid12039948-20] Zhang H, Peters KW, Sun F, Marino CR, Lang J, Burgoyne RD, Frizzell RA (2002). "Cysteine string protein interacts with and modulates the maturation of the cystic fibrosis transmembrane conductance regulator". J. Biol. Chem. 277 (32): 28948–58. doi:10.1074/jbc.M111706200. PMID 12039948.

[pmid11707463-21] Cheng J, Moyer BD, Milewski M, Loffing J, Ikeda M, Mickle JE, Cutting GR, Li M, Stanton BA, Guggino WB (2002). "A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression". J. Biol. Chem. 277 (5): 3520–9. doi:10.1074/jbc.M110177200. PMID 11707463.

[pmid12471024-22] Gentzsch M, Cui L, Mengos A, Chang XB, Chen JH, Riordan JR (2003). "The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins". J. Biol. Chem. 278 (8): 6440–9. doi:10.1074/jbc.M211050200. PMID 12471024.

[pmid11051556-23] Wang S, Yue H, Derin RB, Guggino WB, Li M (2000). "Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity". Cell 103 (1): 169–79. doi:10.1016/S0092-8674(00)00096-9. PMID 11051556.

[pmid11956211-24] Liedtke CM, Yun CH, Kyle N, Wang D (2002). "Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor". J. Biol. Chem. 277 (25): 22925–33. doi:10.1074/jbc.M201917200. PMID 11956211.

[pmid12403779-25] Park M, Ko SB, Choi JY, Muallem G, Thomas PJ, Pushkin A, Lee MS, Kim JY, Lee MG, Muallem S, Kurtz I (2002). "The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3". J. Biol. Chem. 277 (52): 50503–9. doi:10.1074/jbc.M201862200. PMID 12403779.

[pmid12209004-26] Cormet-Boyaka E, Di A, Chang SY, Naren AP, Tousson A, Nelson DJ, Kirk KL (2002). "CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex". Proc. Natl. Acad. Sci. U.S.A. 99 (19): 12477–82. Bibcode:2002PNAS...9912477C. doi:10.1073/pnas.192203899. PMC 129470. PMID 12209004.

[pmid12615054-27] Hegedüs T, Sessler T, Scott R, Thelin W, Bakos E, Váradi A, Szabó K, Homolya L, Milgram SL, Sarkadi B (2003). "C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins". Biochem. Biophys. Res. Commun. 302 (3): 454–61. doi:10.1016/S0006-291X(03)00196-7. PMID 12615054.

[pmid9613608-28] Wang S, Raab RW, Schatz PJ, Guggino WB, Li M (1998). "Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)". FEBS Lett. 427 (1): 103–8. doi:10.1016/S0014-5793(98)00402-5. PMID 9613608.

[pmid10852925-29] Moyer BD, Duhaime M, Shaw C, Denton J, Reynolds D, Karlson KH, Pfeiffer J, Wang S, Mickle JE, Milewski M, Cutting GR, Guggino WB, Li M, Stanton BA (2000). "The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane". J. Biol. Chem. 275 (35): 27069–74. doi:10.1074/jbc.M004951200. PMID 10852925.

[pmid9671706-30] Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ (1998). "A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins". Proc. Natl. Acad. Sci. U.S.A. 95 (15): 8496–501. Bibcode:1998PNAS...95.8496H. doi:10.1073/pnas.95.15.8496. PMC 21104. PMID 9671706.

[pmid10893422-31] Sun F, Hug MJ, Lewarchik CM, Yun CH, Bradbury NA, Frizzell RA (2000). "E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells". J. Biol. Chem. 275 (38): 29539–46. doi:10.1074/jbc.M004961200. PMID 10893422.

[pmid9384384-32] Naren AP, Nelson DJ, Xie W, Jovov B, Pevsner J, Bennett MK, Benos DJ, Quick MW, Kirk KL (1997). "Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms". Nature 390 (6657): 302–5. Bibcode:1997Natur.390..302N. doi:10.1038/36882. PMID 9384384.

[33] The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org , accessed 2013-12-12

リンク元	「嚢胞性線維症膜貫通調節蛋白質」「CFTR gene」
関連記事	「conductance」「transmembrane」「regulator」「transmembrane conductance」「cystic」

匿名

検索

案内

案内

cystic fibrosis transmembrane conductance regulator