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Calcium activated chloride channel (CaCC) C

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).

Overview

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Chloride channels activated by intracellular calcium (CaCC) are widely expressed in excitable and non-excitable cells where they perform diverse functions [10]. The molecular nature of CaCC has been uncertain with both CLCA, TWEETY and BEST genes having been considered as likely candidates [7,11,14]. 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 [18]. 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 [11] and form chloride channels that are activated by physiological concentrations of Ca2+, but whether such activation is direct is not known [11]. 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. [7]. 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 [6,12]. TMEM16A (anoctamin 1; Ano 1) produces Ca2+-activated Cl- currents with kinetics similar to native CaCC currents recorded from different cell types [2,20-21,24]. Knockdown of TMEM16A greatly reduces currents mediated by calcium-activated chloride channels in submandibular gland cells [24] and smooth muscle cells from pulmonary artery [15]. In TMEM16A(-/-) mice secretion of Ca2+-dependent Cl- secretion by several epithelia is reduced [17,20]. Alternative splicing regulates the voltage- and Ca2+- dependence of TMEM16A and such processing may be tissue-specific manner and thus contribute to functional diversity [8]. There are also reports that TMEM16B (anoctamin 2; Ano 2) supports CaCC activity (e.g.[19]) and in TMEM16B(-/-) mice Ca-activated Cl- currents in the main olfactory epithelium (MOE) and in the vomeronasal organ are virtually absent [1].

Channels and Subunits

708
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CaCC C Show summary »


Target Id 708
Nomenclature CaCC
Previous and unofficial names DOG1 | ORAOV2 | TAOS2 | TMEM16A | oral cancer overexpressed 2 | transmembrane protein 16A | anoctamin 1, calcium activated chloride channel | anoctamin 1
Genes ANO1 (Hs), Ano1 (Mm), Ano1 (Rn)
Ensembl ID ENSG00000131620 (Hs), ENSMUSG00000031075 (Mm), ENSRNOG00000020865 (Rn)
UniProtKB AC Q5XXA6 (Hs), Q8BHY3 (Mm)
Endogenous activators
intracellular Ca2+
Selective inhibitors
Ani9 pIC50 7.0 [22]
crofelemer pIC50 5.2 [23]
Endogenous channel blockers
Ins(3,4,5,6)P4
Channel blockers
fluoxetine
niflumic acid
flufenamic acid
mibefradil
9-anthroic acid
DCDPC
DIDS
NPPB
SITS
tannic acid
Functional characteristics γ = 0.5-5 pS; permeability sequence, SCN- > NO3 -> I- > Br- > Cl- > F-; relative permeability of SCN-:Cl- ~8. I-:Cl- ~3, aspartate:Cl- ~0.15, outward rectification (decreased by increasing [Ca2+]i); sensitivity to activation by [Ca2+]i decreased at hyperpolarized potentials; slow activation at positive potentials (accelerated by increasing [Ca2+]i); rapid deactivation at negative potentials, deactivation kinetics modulated by anions binding to an external site; modulated by redox status
Comment A CaCC (TMEM16A) potentiator compound (ETD002, undisclosed structure; acquired by Roche from Enterprise Therapeutics) has entered Phase 1 clinical evaluation as a novel approach that has potential to provide benefit to all patients with cystic fibrosis. Up-regulating chloride transport via CaCC is proposed to mitigate the effect of loss of chloride transport via CFTR in CF. See Enterprise Therapeutics' reports of CaCC potentiator ETX001 for more detailed background information [3-4].

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How to cite this family page

Database page citation:

Calcium activated chloride channel (CaCC). Accessed on 23/09/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=130.

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.