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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
Chloride channels activated by intracellular Ca2+ (CaCC) are widely expressed in excitable and non-excitable cells where they perform diverse functions [24]. CaCCs are activated by a rise in intracellular free Ca2+ concentration ([Ca2+]i), typically following activation of Gq protein coupled receptors (GqPCR). This section centres on CaCC channels encoded by the TMEM16A gene (HUGO gene nomenclature: Anoctamin 1). The TMEM16 family consists of 10 paralogs (TMEM16A-K; Anoctamin 1-10). The TMEM16A and TMEM16B genes (ANO1 and ANO2) encode for CaCCs, while the other members function as lipid scramblases or have combined scramblase and non-selective ion channel function [1,17,25,40,45]. TMEM16A has a broad tissue distribution and a variety of established cellular roles, while the main physiological role for TMEM16B identified thus far is in olfaction [15,30]. Alternative splicing regulates the voltage- and Ca2+-dependence of TMEM16A and such post-transcriptional process may be tissue-specific and contribute to functional diversity [18]. TMEM16A is a potential drug target for a variety of conditions spanning from respiratory to vascular (see "Comments" section for further detail).
Channels and Subunits
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CaCC C Show summary »
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Comments
How to cite this family page
Database page citation:
Henry Danahay, Martin Gosling, Paolo Tammaro. Calcium activated chloride channel (CaCC). Accessed on 10/09/2025. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=130.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Mathie AA, Peters JA, Veale EL, Striessnig J, Kelly E, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Ion channels. Br J Pharmacol. 180 Suppl 2:S145-S222.
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Therapeutic indications: TMEM16A regulates a wide variety of physiological processes ranging from nociception to smooth muscle contraction and epithelial secretion [28]. In airway epithelial cells, TMEM16A expression is enhanced by inflammatory stimuli that also lead to goblet cell metaplasia and increased mucus secretion. Thus, pharmacological modulation of TMEM16A could help to improve mucociliary clearance in cystic fibrosis (CF) and chronic obstructive respiratory disease [11,19]. TMEM16A activation might also be of potential therapeutic benefit in Sjögren's syndrome. Given the established role of TMEM16A role in smooth muscle and cerebral pericyte contraction, pharmacological inhibitors of TMEM16A are expected to promote vasodilation and could have therapeutic use in a range of diseases of altered vessel tone including stoke, hypertension and vascular dementia [4,22]. Other suggested therapeutic indications in which TMEM16A could be targeted include neuropathic pain, given the identified role of TMEM16A in dorsal root ganglion (DRG) neurons [34]. TMEM16A is also expressed in interstitial cells of Cajal and may be involved in the control of gastric emptying and motility [8]; thus, TMEM16A modulators could be used to modulate gastric contractility. TMEM16A was also reported in the smooth muscle of the bladder, uterus, and internal urethral sphincter; therefore, TMEM16A modulators could have a role in the treatment of overactive bladder and urinary incontinence [16] and to foster myometrium relaxation [52]. TMEM16A is overexpressed in a variety of cancer types and TMEM16A inhibitors have been suggested as a potential anticancer treatment [27,43].
Pharmacology: A CaCC (TMEM16A) activator compound (GDC-6988/ETD002, undisclosed structure; acquired by Roche from Enterprise Therapeutics) entered Phase 1 clinical evaluation as a novel approach that has potential to provide benefit to all patients with cystic fibrosis (CF) (mentioned in [41]). Up-regulating chloride transport via CaCC is proposed to mitigate the effect of loss of Cl- transport via CFTR in CF. See Enterprise Therapeutics' reports of CaCC potentiator ETX001 for more detailed background information [10,13]. The compound Eact has been reported to directly activate TMEM16A [51]. However, recent data have challenged this direct activation of TMEM16A and indicate that Eact induces an increase in [Ca2+]i through an agonist effect on TRPV1 and TRPV4 [20,35]. Many of the listed TMEM16A channel blockers are recognised as being unselective [3,6,21]. Ani9 demonstrates selectivity for TMEM16A versus TMEM16B [46] and, in contrast to several of the other inhibitors, (i) has no effects on intracellular Ca2+ signalling in human airway epithelial cells [12] and (ii) does not affect a range of other ion current types [3]. Ani9 possess an imine/hydrazone group that might render the compound unstable and potentially reactive in vivo. TMinh-23 is one the most potent TMEM16A inhibitors reported thus far (IC50 ~30 nM) [9,50]. However, the selectivity of this compound is not fully defined, and the compound might be metabolically unstable in vivo due to potential hydrolysis of one or both amide groups present in this molecule. TMEM16A is inhibited by the therapeutic drugs tamsulosin (IC50 ~ 7 μM) [32]. The anthelminthic niclosamide was also reported to inhibit TMEM16A [36], but further studies demonstrated that niclosamide can act both as an inhibitor or an activator depending on the membrane potential and [Ca2+]i [12,29,33]. A range of natural compounds including gallotannins [37], evodiamine and rutecarpine [53], theaflavin [47] and allicin [5] are non-selective, low potency TMEM16A inhibitors. CaCC currents in CFPAC-1 have also been reported to be inhibited by Ins(3,4,5,6)P4 [26]. Complex effects on native CaCC and cloned TMEM16A and TMEM16B currents have been observed for a range of compounds including extracellular niflumic acid; DCDPC and 9-anthroic acid (but not DIDS) enhancing and inhibiting inwardly and outwardly directed currents in a manner dependent upon [Ca2+]i and membrane potential [7,42,44,48] (and [31] for summary). Blockade of CaCC currents by niflumic acid, DIDS and 9-anthroic acid is voltage-dependent, whereas block by NPPB is voltage-independent [24]. Considerable crossover in pharmacology with large conductance Ca2+-activated K+ channels also exists (see [23] for overview).