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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).
Chloride channels activated by intracellular calcium (CaCC) are widely expressed in excitable and non-excitable cells where they perform diverse functions . The molecular nature of CaCC has been uncertain with both CLCA, TWEETY and BEST genes having been considered as likely candidates [5,9,12]. It is now accepted that CLCA expression products are unlikely to form channels per se and probably function as cell adhesion proteins, or are secreted . Similarly, TWEETY gene products do not recapictulate the properties of endogenous CaCC. The bestrophins encoded by genes BEST1-4 have a topology more consistent with ion channels  and form chloride channels that are activated by physiological concentrations of Ca2+, but whether such activation is direct is not known . However, currents generated by bestrophin over-expression do not resemble native CaCC currents. The evidence for and against bestrophin proteins forming CaCC is critically reviewed by Duran et al. . Recently, a new gene family, TMEM16 (anoctamin) consisting of 10 members (TMEM16A-K; anoctamin 1-10) has been identified and there is firm evidence that some of these members form chloride channels [4,10]. TMEM16A (anoctamin 1; Ano 1) produces Ca2+-activated Cl- currents with kinetics similar to native CaCC currents recorded from different cell types [2,18-19,21]. Knockdown of TMEM16A greatly reduces currents mediated by calcium-activated chloride channels in submandibular gland cells  and smooth muscle cells from pulmonary artery . In TMEM16A(-/-) mice secretion of Ca2+-dependent Cl- secretion by several epithelia is reduced [15,18]. Alternative splicing regulates the voltage- and Ca2+- dependence of TMEM16A and such processing may be tissue-specific manner and thus contribute to functional diversity . There are also reports that TMEM16B (anoctamin 2; Ano 2) supports CaCC activity (e.g.) and in TMEM16B(-/-) mice Ca-activated Cl- currents in the main olfactory epithelium (MOE) and in the vomeronasal organ are virtually absent .
1. Billig GM, Pál B, Fidzinski P, Jentsch TJ. (2011) Ca2+-activated Cl− currents are dispensable for olfaction. Nat. Neurosci., 14 (6): 763-9. [PMID:21516098]
2. Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ. (2008) TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science, 322 (5901): 590-4. [PMID:18772398]
3. De La Fuente R, Namkung W, Mills A, Verkman AS. (2008) Small-molecule screen identifies inhibitors of a human intestinal calcium-activated chloride channel. Mol. Pharmacol., 73 (3): 758-68. [PMID:18083779]
4. Duran C, Hartzell HC. (2011) Physiological roles and diseases of Tmem16/Anoctamin proteins: are they all chloride channels?. Acta Pharmacol. Sin., 32 (6): 685-92. [PMID:21642943]
5. Duran C, Thompson CH, Xiao Q, Hartzell HC. (2010) Chloride channels: often enigmatic, rarely predictable. Annu. Rev. Physiol., 72: 95-121. [PMID:19827947]
6. Ferrera L, Caputo A, Ubby I, Bussani E, Zegarra-Moran O, Ravazzolo R, Pagani F, Galietta LJ. (2009) Regulation of TMEM16A chloride channel properties by alternative splicing. J. Biol. Chem., 284 (48): 33360-8. [PMID:19819874]
7. Greenwood IA, Leblanc N. (2007) Overlapping pharmacology of Ca2+-activated Cl- and K+ channels. Trends Pharmacol. Sci., 28 (1): 1-5. [PMID:17150263]
8. Hartzell C, Putzier I, Arreola J. (2005) Calcium-activated chloride channels. Annu. Rev. Physiol., 67: 719-58. [PMID:15709976]
9. Hartzell HC, Qu Z, Yu K, Xiao Q, Chien LT. (2008) Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. Physiol. Rev., 88 (2): 639-72. [PMID:18391176]
10. Kunzelmann K, Tian Y, Martins JR, Faria D, Kongsuphol P, Ousingsawat J, Thevenod F, Roussa E, Rock J, Schreiber R. (2011) Anoctamins. Pflugers Arch., 462 (2): 195-208. [PMID:21607626]
11. Leblanc N, Ledoux J, Saleh S, Sanguinetti A, Angermann J, O'Driscoll K, Britton F, Perrino BA, Greenwood IA. (2005) Regulation of calcium-activated chloride channels in smooth muscle cells: a complex picture is emerging. Can. J. Physiol. Pharmacol., 83 (7): 541-56. [PMID:16091780]
12. Loewen ME, Forsyth GW. (2005) Structure and function of CLCA proteins. Physiol. Rev., 85 (3): 1061-92. [PMID:15987802]
13. Manoury B, Tamuleviciute A, Tammaro P. (2010) TMEM16A/anoctamin 1 protein mediates calcium-activated chloride currents in pulmonary arterial smooth muscle cells. J. Physiol. (Lond.), 588 (Pt 13): 2305-14. [PMID:20421283]
14. Namkung W, Phuan PW, Verkman AS. (2011) TMEM16A inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells. J. Biol. Chem., 286 (3): 2365-74. [PMID:21084298]
15. Ousingsawat J, Martins JR, Schreiber R, Rock JR, Harfe BD, Kunzelmann K. (2009) Loss of TMEM16A causes a defect in epithelial Ca2+-dependent chloride transport. J. Biol. Chem., 284 (42): 28698-703. [PMID:19679661]
16. Patel AC, Brett TJ, Holtzman MJ. (2009) The role of CLCA proteins in inflammatory airway disease. Annu. Rev. Physiol., 71: 425-49. [PMID:18954282]
17. Pifferi S, Dibattista M, Menini A. (2009) TMEM16B induces chloride currents activated by calcium in mammalian cells. Pflugers Arch., 458 (6): 1023-38. [PMID:19475416]
18. Rock JR, O'Neal WK, Gabriel SE, Randell SH, Harfe BD, Boucher RC, Grubb BR. (2009) Transmembrane protein 16A (TMEM16A) is a Ca2+-regulated Cl- secretory channel in mouse airways. J. Biol. Chem., 284 (22): 14875-80. [PMID:19363029]
19. Schroeder BC, Cheng T, Jan YN, Jan LY. (2008) Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell, 134 (6): 1019-29. [PMID:18805094]
20. 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]
21. Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM et al.. (2008) TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature, 455 (7217): 1210-5. [PMID:18724360]
Database page citation:
Calcium activated chloride channel. Accessed on 27/04/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=130.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Other ion channels. Br J Pharmacol. 172: 5942-5955.