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- Chloride channels
Overview
Chloride channels are a functionally and structurally diverse group of anion selective channels involved in processes including the regulation of the excitability of neurones, skeletal, cardiac and smooth muscle, cell volume regulation, transepithelial salt transport, the acidification of internal and extracellular compartments, the cell cycle and apoptosis (reviewed in [1]). Excluding the transmittergated GABAA and glycine receptors (see separate tables), well characterised chloride channels can be classified as certain members of the voltage-sensitive ClC subfamily, calcium-activated channels, high (maxi) conductance channels, the cystic fibrosis transmembrane conductance regulator (CFTR) and volume regulated channels [9]. No official recommendation exists regarding the classification of chloride channels. Functional chloride channels that have been cloned from, or characterised within, mammalian tissues are listed with the exception of several classes of intracellular channels (e.g. CLIC) that are reviewed by in [2].
Further reading
* Key recommended reading is highlighted with an asterisk
Accardi A, Picollo A. (2010) CLC channels and transporters: proteins with borderline personalities. Biochim Biophys Acta, 1798 (8): 1457-64. [PMID:20188062]
* Adkins GB, Curtis MJ. (2015) Potential role of cardiac chloride channels and transporters as novel therapeutic targets. Pharmacol Ther, 145: 67-75. [PMID:25160469]
Alekov AK, Fahlke C. (2008) Anion channels: regulation of ClC-3 by an orphan second messenger. Curr Biol, 18 (22): R1061-4. [PMID:19036336]
Aleksandrov AA, Aleksandrov LA, Riordan JR. (2007) CFTR (ABCC7) is a hydrolyzable-ligand-gated channel. Pflugers Arch, 453 (5): 693-702. [PMID:17021796]
Amaral MD, Kunzelmann K. (2007) Molecular targeting of CFTR as a therapeutic approach to cystic fibrosis. Trends Pharmacol Sci, 28 (7): 334-41. [PMID:17573123]
Aromataris EC, Rychkov GY. (2006) ClC-1 chloride channel: Matching its properties to a role in skeletal muscle. Clin Exp Pharmacol Physiol, 33 (11): 1118-23. [PMID:17042925]
Ashlock MA, Olson ER. (2011) Therapeutics development for cystic fibrosis: a successful model for a multisystem genetic disease. Annu Rev Med, 62: 107-25. [PMID:21226613]
Babini E, Pusch M. (2004) A two-holed story: structural secrets about ClC proteins become unraveled?. Physiology (Bethesda), 19: 293-9. [PMID:15381758]
Best L, Brown PD, Sener A, Malaisse WJ. (2010) Electrical activity in pancreatic islet cells: The VRAC hypothesis. Islets, 2 (2): 59-64. [PMID:21099297]
Chen TY. (2005) Structure and function of clc channels. Annu Rev Physiol, 67: 809-39. [PMID:15709979]
Chen TY, Hwang TC. (2008) CLC-0 and CFTR: chloride channels evolved from transporters. Physiol Rev, 88 (2): 351-87. [PMID:18391167]
Cuthbert AW. (2011) New horizons in the treatment of cystic fibrosis. Br J Pharmacol, 163 (1): 173-83. [PMID:21108631]
Duan D. (2009) Phenomics of cardiac chloride channels: the systematic study of chloride channel function in the heart. J Physiol (Lond.), 587 (Pt 10): 2163-77. [PMID:19171656]
Duan DD. (2011) The ClC-3 chloride channels in cardiovascular disease. Acta Pharmacol Sin, 32 (6): 675-84. [PMID:21602838]
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]
Duran C, Thompson CH, Xiao Q, Hartzell HC. (2010) Chloride channels: often enigmatic, rarely predictable. Annu Rev Physiol, 72: 95-121. [PMID:19827947]
Dutzler R. (2007) A structural perspective on ClC channel and transporter function. FEBS Lett, 581 (15): 2839-44. [PMID:17452037]
Edwards JC, Kahl CR. (2010) Chloride channels of intracellular membranes. FEBS Lett, 584 (10): 2102-11. [PMID:20100480]
Fahlke C. (2001) Ion permeation and selectivity in ClC-type chloride channels. Am J Physiol Renal Physiol, 280 (5): F748-57. [PMID:11292616]
Fahlke C, Fischer M. (2010) Physiology and pathophysiology of ClC-K/barttin channels. Front Physiol, 1: 155. [PMID:21423394]
Ferrera L, Caputo A, Galietta LJ. (2010) TMEM16A protein: a new identity for Ca(2+)-dependent Cl⁻ channels. Physiology (Bethesda), 25 (6): 357-63. [PMID:21186280]
Fiedorczuk K, Chen J. (2022) Mechanism of CFTR correction by type I folding correctors. Cell, 185 (1): 158-168.e11. [PMID:34995514]
Gadsby DC, Vergani P, Csanády L. (2006) The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature, 440 (7083): 477-83. [PMID:16554808]
Galietta LJ. (2009) The TMEM16 protein family: a new class of chloride channels?. Biophys J, 97 (12): 3047-53. [PMID:20006941]
Greenwood IA, Leblanc N. (2007) Overlapping pharmacology of Ca2+-activated Cl- and K+ channels. Trends Pharmacol Sci, 28 (1): 1-5. [PMID:17150263]
Guan YY, Wang GL, Zhou JG. (2006) The ClC-3 Cl- channel in cell volume regulation, proliferation and apoptosis in vascular smooth muscle cells. Trends Pharmacol Sci, 27 (6): 290-6. [PMID:16697056]
Hartzell C, Putzier I, Arreola J. (2005) Calcium-activated chloride channels. Annu Rev Physiol, 67: 719-58. [PMID:15709976]
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]
* Huang F, Wong X, Jan LY. (2012) International Union of Basic and Clinical Pharmacology. LXXXV: calcium-activated chloride channels. Pharmacol Rev, 64 (1): 1-15. [PMID:22090471]
Jentsch TJ. (2008) CLC chloride channels and transporters: from genes to protein structure, pathology and physiology. Crit Rev Biochem Mol Biol, 43 (1): 3-36. [PMID:18307107]
* Kamaleddin MA. (2018) Molecular, biophysical, and pharmacological properties of calcium-activated chloride channels. J Cell Physiol, 233 (2): 787-798. [PMID:28121009]
Kirk KL, Wang W. (2011) A unified view of cystic fibrosis transmembrane conductance regulator (CFTR) gating: combining the allosterism of a ligand-gated channel with the enzymatic activity of an ATP-binding cassette (ABC) transporter. J Biol Chem, 286 (15): 12813-9. [PMID:21296873]
Krämer BK, Bergler T, Stoelcker B, Waldegger S. (2008) Mechanisms of Disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance. Nat Clin Pract Nephrol, 4 (1): 38-46. [PMID:18094726]
* Kunzelmann K. (2015) TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca(2+) and cell volume. Trends Biochem Sci, 40 (9): 535-43. [PMID:26254230]
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]
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]
Loewen ME, Forsyth GW. (2005) Structure and function of CLCA proteins. Physiol Rev, 85 (3): 1061-92. [PMID:15987802]
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]
Mulligan SJ, MacVicar BA. (2006) VRACs CARVe a path for novel mechanisms of communication in the CNS. Sci STKE, 2006 (357): pe42. [PMID:17047222]
Nilius B, Droogmans G. (2003) Amazing chloride channels: an overview. Acta Physiol Scand, 177 (2): 119-47. [PMID:12558550]
Noy E, Senderowitz H. (2011) Combating cystic fibrosis: in search for CF transmembrane conductance regulator (CFTR) modulators. ChemMedChem, 6 (2): 243-51. [PMID:21275046]
Okada Y. (2006) Cell volume-sensitive chloride channels: phenotypic properties and molecular identity. Contrib Nephrol, 152: 9-24. [PMID:17065805]
Okada Y, Sato K, Numata T. (2009) Pathophysiology and puzzles of the volume-sensitive outwardly rectifying anion channel. J Physiol (Lond.), 587 (Pt 10): 2141-9. [PMID:19171657]
Patel AC, Brett TJ, Holtzman MJ. (2009) The role of CLCA proteins in inflammatory airway disease. Annu Rev Physiol, 71: 425-49. [PMID:18954282]
* Pedersen SF, Okada Y, Nilius B. (2016) Biophysics and Physiology of the Volume-Regulated Anion Channel (VRAC)/Volume-Sensitive Outwardly Rectifying Anion Channel (VSOR). Pflugers Arch, 468 (3): 371-83. [PMID:26739710]
* Peretti M, Angelini M, Savalli N, Florio T, Yuspa SH, Mazzanti M. (2015) Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets. Biochim Biophys Acta, 1848 (10 Pt B): 2523-31. [PMID:25546839]
Planells-Cases R, Jentsch TJ. (2009) Chloride channelopathies. Biochim Biophys Acta, 1792 (3): 173-89. [PMID:19708126]
Plans V, Rickheit G, Jentsch TJ. (2009) Physiological roles of CLC Cl(-)/H (+) exchangers in renal proximal tubules. Pflugers Arch, 458 (1): 23-37. [PMID:18853181]
Puljak L, Kilic G. (2006) Emerging roles of chloride channels in human diseases. Biochim Biophys Acta, 1762 (4): 404-13. [PMID:16457993]
Pusch M, Accardi A, Liantonio A, Guida P, Traverso S, Camerino DC, Conti F. (2002) Mechanisms of block of muscle type CLC chloride channels (Review). Mol Membr Biol, 19 (4): 285-92. [PMID:12512775]
Pusch M, Zifarelli G, Murgia AR, Picollo A, Babini E. (2006) Channel or transporter? The CLC saga continues. Exp Physiol, 91 (1): 149-52. [PMID:16179405]
Riordan JR. (2005) Assembly of functional CFTR chloride channels. Annu Rev Physiol, 67: 701-18. [PMID:15709975]
Riquelme G. (2009) Placental chloride channels: a review. Placenta, 30 (8): 659-69. [PMID:19604577]
* Sabirov RZ, Merzlyak PG, Islam MR, Okada T, Okada Y. (2016) The properties, functions, and pathophysiology of maxi-anion channels. Pflugers Arch, 468 (3): 405-20. [PMID:26733413]
Sabirov RZ, Okada Y. (2009) The maxi-anion channel: a classical channel playing novel roles through an unidentified molecular entity. J Physiol Sci, 59 (1): 3-21. [PMID:19340557]
Sardini A, Amey JS, Weylandt KH, Nobles M, Valverde MA, Higgins CF. (2003) Cell volume regulation and swelling-activated chloride channels. Biochim Biophys Acta, 1618 (2): 153-62. [PMID:14729152]
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]
Suzuki M, Mizuno A. (2004) A novel human Cl(-) channel family related to Drosophila flightless locus. J Biol Chem, 279 (21): 22461-8. [PMID:15010458]
Verkman AS, Galietta LJ. (2009) Chloride channels as drug targets. Nat Rev Drug Discov, 8 (2): 153-71. [PMID:19153558]
* Zegarra-Moran O, Galietta LJ. (2017) CFTR pharmacology. Cell Mol Life Sci, 74 (1): 117-128. [PMID:27704174]
References
1. Duran C, Thompson CH, Xiao Q, Hartzell HC. (2010) Chloride channels: often enigmatic, rarely predictable. Annu Rev Physiol, 72: 95-121. [PMID:19827947]
2. Edwards JC, Kahl CR. (2010) Chloride channels of intracellular membranes. FEBS Lett, 584 (10): 2102-11. [PMID:20100480]
3. Gururaja Rao S, Ponnalagu D, Patel NJ, Singh H. (2018) Three Decades of Chloride Intracellular Channel Proteins: From Organelle to Organ Physiology. Curr Protoc Pharmacol, 80 (1): 11.21.1-11.21.17. [PMID:30040212]
4. Lambert S, Oberwinkler J. (2005) Characterization of a proton-activated, outwardly rectifying anion channel. J Physiol (Lond.), 567 (Pt 1): 191-213. [PMID:15961423]
5. Matchkov VV, Aalkjaer C, Nilsson H. (2004) A cyclic GMP-dependent calcium-activated chloride current in smooth-muscle cells from rat mesenteric resistance arteries. J Gen Physiol, 123 (2): 121-34. [PMID:14718479]
6. Matchkov VV, Larsen P, Bouzinova EV, Rojek A, Boedtkjer DM, Golubinskaya V, Pedersen FS, Aalkjaer C, Nilsson H. (2008) Bestrophin-3 (vitelliform macular dystrophy 2-like 3 protein) is essential for the cGMP-dependent calcium-activated chloride conductance in vascular smooth muscle cells. Circ Res, 103 (8): 864-72. [PMID:18776041]
7. Piper AS, Large WA. (2004) Single cGMP-activated Ca(+)-dependent Cl(-) channels in rat mesenteric artery smooth muscle cells. J Physiol (Lond.), 555 (Pt 2): 397-408. [PMID:14724180]
8. Tsumura T, Hazama A, Miyoshi T, Ueda S, Okada Y. (1998) Activation of cAMP-dependent C1- currents in guinea-pig paneth cells without relevant evidence for CFTR expression. J Physiol (Lond.), 512 ( Pt 3): 765-77. [PMID:9769420]
9. Verkman AS, Galietta LJ. (2009) Chloride channels as drug targets. Nat Rev Drug Discov, 8 (2): 153-71. [PMID:19153558]
How to cite this family page
Database page citation:
Chloride channels. Accessed on 20/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=120.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Mathie A, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. Br J Pharmacol. 176 Issue S1: S142-228.
Other chloride channels
In addition to some intracellular chloride channels that are not considered here, plasma membrane channels other than those listed have been functionally described. Many cells and tissues contain outwardly rectifying chloride channels (ORCC) that may correspond to VRAC active under isotonic conditions. A cyclic AMP-activated Cl- channel that does not correspond to CFTR has been described in intestinal Paneth cells [8]. A Cl channel activated by cyclic GMP with a dependence on raised intracellular Ca2+ has been recorded in various vascular smooth muscle cells types, which has a pharmacology and biophysical characteristics very different from the 'conventional' CaCC [5,7]. It has been proposed that bestrophin-3 (BEST3, Q8N1M1) is an essential component of the cyclic GMP-activated channel [6]. A proton-activated, outwardly rectifying anion channel has also been described [4].
The chloride intracellular channel proteins (CLICs) are non-canonical ion channels with six homologs, distinct from most ion channels in that they have both soluble and integral membrane forms. The physiological role of CLICs appears to be maintenance of intracellular membranes, which is associated with tubulogenesis but may involve other substructures [3]. .