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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
CFTR, a 12TM, ABC transporter-type protein, is a cAMP-regulated epithelial cell membrane Cl- channel involved in normal fluid transport across various epithelia. Of the 1700 mutations identified in CFTR, the most common is the deletion mutant ΔF508 (a class 2 mutation) which results in impaired trafficking of CFTR and reduces its incorporation into the plasma membrane causing cystic fibrosis (reviewed in ). Channels carrying the ΔF508 mutation that do traffic to the plasma membrane demonstrate gating defects. Thus, pharmacological restoration the function of the ΔF508 mutant would require a compound that embodies ‘corrector’ (i.e. facilitates folding and trafficking to the cell surface) and ‘potentiator’ (i.e. promotes opening of channels at the cell surface) activities . In addition to acting as an anion channel per se, CFTR may act as a regulator of several other conductances including inhibition of the epithelial Na channel (ENaC), calcium activated chloride channels (CaCC) and volume regulated anion channel (VRAC), activation of the outwardly rectifying chloride channel (ORCC), and enhancement of the sulphonylurea sensitivity of the renal outer medullary potassium channel (ROMK2), (reviewed in ). CFTR also regulates TRPV4, which provides the Ca2+ signal for regulatory volume decrease in airway epithelia . The activities of CFTR and the chloride-bicarbonate exchangers SLC26A3 (DRA) and SLC26A6 (PAT1) are mutually enhanced by a physical association between the regulatory (R) domain of CFTR and the STAS domain of the SCL26 transporters, an effect facilitated by PKA-mediated phosphorylation of the R domain of CFTR .
1. Aleksandrov AA, Aleksandrov LA, Riordan JR. (2007) CFTR (ABCC7) is a hydrolyzable-ligand-gated channel. Pflugers Arch., 453 (5): 693-702. [PMID:17021796]
2. Arniges M, Vázquez E, Fernández-Fernández JM, Valverde MA. (2004) Swelling-activated Ca2+ entry via TRPV4 channel is defective in cystic fibrosis airway epithelia. J. Biol. Chem., 279 (52): 54062-8. [PMID:15489228]
3. Cuthbert AW. (2011) New horizons in the treatment of cystic fibrosis. Br. J. Pharmacol., 163 (1): 173-83. [PMID:21108631]
4. Fuller MD, Thompson CH, Zhang ZR, Freeman CS, Schay E, Szakács G, Bakos E, Sarkadi B, McMaster D, French RJ et al.. (2007) State-dependent inhibition of cystic fibrosis transmembrane conductance regulator chloride channels by a novel peptide toxin. J. Biol. Chem., 282 (52): 37545-55. [PMID:17951250]
5. Ko SB, Zeng W, Dorwart MR, Luo X, Kim KH, Millen L, Goto H, Naruse S, Soyombo A, Thomas PJ et al.. (2004) Gating of CFTR by the STAS domain of SLC26 transporters. Nat. Cell Biol., 6 (4): 343-50. [PMID:15048129]
6. Muallem D, Vergani P. (2009) Review. ATP hydrolysis-driven gating in cystic fibrosis transmembrane conductance regulator. Philos. Trans. R. Soc. Lond., B, Biol. Sci., 364 (1514): 247-55. [PMID:18957373]
7. Nilius B, Droogmans G. (2003) Amazing chloride channels: an overview. Acta Physiol. Scand., 177 (2): 119-47. [PMID:12558550]
8. Pedemonte N, Boido D, Moran O, Giampieri M, Mazzei M, Ravazzolo R, Galietta LJ. (2007) Structure-activity relationship of 1,4-dihydropyridines as potentiators of the cystic fibrosis transmembrane conductance regulator chloride channel. Mol. Pharmacol., 72 (1): 197-207. [PMID:17452495]
9. Sheppard DN, Welsh MJ. (1992) Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents. J. Gen. Physiol., 100 (4): 573-91. [PMID:1281220]
10. Sloane PA, Rowe SM. (2010) Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis. Curr Opin Pulm Med, 16 (6): 591-7. [PMID:20829696]
11. Tradtrantip L, Namkung W, Verkman AS. (2010) Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol. Pharmacol., 77 (1): 69-78. [PMID:19808995]
12. Verkman AS, Galietta LJ. (2009) Chloride channels as drug targets. Nat Rev Drug Discov, 8 (2): 153-71. [PMID:19153558]
Database page citation:
CFTR. Accessed on 27/11/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=129.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Catterall WA, Spedding M, Peters JA and Harmar AJ, CGTP Collaborators. (2013) The Concise Guide to PHARMACOLOGY 2013/14: Ion Channels. Br J Pharmacol. 170: 1607–1651.