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. Author manuscript; available in PMC: 2025 Sep 16.
Published before final editing as: J Physiol. 2025 Sep 14:10.1113/JP289160. doi: 10.1113/JP289160

TMEM16A in gastrointestinal and vascular smooth muscle contractility

Sadik Taskin Tas 1, Marc O Anderson 1,2, Onur Cil 1
PMCID: PMC12435907  NIHMSID: NIHMS2107098  PMID: 40946329

Abstract

Calcium-activated Cl− channels (CaCC) are widely-expressed proteins which regulate various physiological functions. TMEM16A is a CaCC expressed in the gastrointestinal and cardiovascular systems, where it is a major regulator of tissue contraction. In this review, we discuss recent advances on the roles of TMEM16A in gastrointestinal and vascular smooth muscle contractility including its segment and cell type-specific effects. We also discuss recent physiological and pharmacological evidence suggesting potential therapeutic utility of TMEM16A modulators in gastrointestinal and cardiovascular diseases associated with altered smooth muscle contractility.

Keywords: Anoctamin-1, ANO1, CaCC, gut motility, vascular tone, vasoconstriction

Introduction

Transmembrane member 16A (TMEM16A, also known as Anoctamin-1 or Ano-1) is a calcium-activated Cl− channel (CaCC) expressed in epithelial, smooth muscle and neuronal cells in certain tissues (Al-Hosni et al., 2022). Like other CaCCs, intracellular Ca2+ elevation is the main driver of TMEM16A channel opening, which results in Cl− efflux. In some contractile tissues such as gut and vasculature, TMEM16A activity is a major regulator of smooth muscle contractility. This review aims to outline the recent advances in roles of TMEM16A in gastrointestinal and vascular smooth muscle contractility. We will also discuss the recent translational studies that suggested TMEM16A as a therapeutic target for gastrointestinal and cardiovascular diseases.

TMEM16A in gastrointestinal tract

Smooth muscle cells, enteric nerves and ICC are the major cell types involved in determining gut contractility which is crucial for propagation of luminal contents, digestion and defecation (Klein et al., 2013). Among these cells, TMEM16A is expressed in all types of ICC throughout the gastrointestinal tract (Gomez-Pinilla et al., 2009). ICC form a network in the gut wall which is connected to enteric nerves via synaptic-like contacts and smooth muscle cells via gap junctions (Horiguchi et al., 2003; Beckett et al., 2005). TMEM16A Cl− channel activation in ICC results in Cl− efflux which is critical for slow wave generation, pacemaker activity, and coordination of Ca2+ transients and contractility in the gut (Zhu et al., 2009; Singh et al., 2014; Hwang et al., 2016). In addition, TMEM16A in certain types of ICC contributes to neuroeffector motor transduction in the gut (Sung et al., 2018; Drumm et al., 2020a). In this section, we summarize recent advances in roles of TMEM16A in contractility and motility including its differential effects in each gut segment.

TMEM16A in stomach and intestine motility

TMEM16A was first demonstrated to be highly expressed in mouse intestine in gene expression studies (Chen et al., 2007). Subsequent immunostaining studies showed prominent TMEM16A protein expression in ICC of the mouse and human gastrointestinal tract (Gomez-Pinilla et al., 2009). After discovery of the function of TMEM16A as a CaCC (Schroeder et al., 2008; Caputo et al., 2008; Yang et al., 2008), its role on gastrointestinal contractility was studied extensively. Initial studies showed that Tmem16a knockout mice have reduced gastric antral contractions (Huang et al., 2009) and absence of slow waves in stomach and small intestine (Hwang et al., 2009) compared to wildtypes. More recent studies focusing on roles of TMEM16A in different types of ICC showed that TMEM16A activation in myenteric ICC is critical for plateau phase of the slow waves in stomach and intestine (Drumm et al., 2017; Baker et al., 2021), whereas TMEM16A in intramuscular ICC is critical for cholinergic neurotransmission in mouse gastric fundus and colon (Sung et al., 2018; Drumm et al., 2020a).

In addition to knockout models, small molecule inhibitors were used extensively in TMEM16A research. However, there has been ongoing concerns regarding the selectivity of some TMEM16A inhibitors (Boedtkjer et al., 2015; Genovese et al., 2023; Al-Hosni et al., 2025). Although the newer inhibitors such as TMinh-23 (Truong et al., 2017) and Ani9 (Seo et al., 2016) are considered more selective than other inhibitors, there has been limited investigation on their selectivity profile. Despite these limitations, TMEM16A inhibitors have provided valuable insights in the gastrointestinal physiology. Initial studies using non-selective Cl− channel blockers showed that niflumic acid can reduce slow waves in mouse gastric antrum and small intestine (Hwang et al., 2009). After discovery of more selective inhibitors of CaCC (De La Fuente et al., 2008) and TMEM16A (Namkung et al., 2011), they were used in physiological studies. Consistent with the earlier niflumic acid data, inhibitors CaCCinh-A01 and benzbromarone were shown to block slow waves in mouse gastrointestinal tissue, although another inhibitor (T16Ainh-A01) had minimal effect in the same setting (Hwang et al., 2016). More recently, TMEM16A inhibitors with nanomolar potency were identified by high-throughput screening and medicinal chemistry (Seo et al., 2016; Truong et al., 2017). Of these newest inhibitors, TMinh-23 was studied for its effects on gastrointestinal contractility and motility. In ex vivo studies, TMinh-23 largely inhibited the amplitude and frequency of spontaneous murine gastric antral contractions at nanomolar concentrations. In mouse small intestine (ileum), TMinh-23 reduced the amplitude of spontaneous ileal contractions, however at much higher micromolar concentrations (Cil et al., 2019). Consistent with its inhibitory effects on gastric contractions, systemic TMinh-23 treatment markedly delayed in vivo gastric emptying in mice (Fig. 1A). Interestingly, TMinh-23 treatment did not affect whole-gut transit time in mice which is primarily determined by intestinal motility (Cil et al., 2019). Furthermore, consistent with its effects on gastric emptying, TMinh-23 treatment improved oral glucose tolerance in mice (Fig. 1B), which is likely due to slower glucose delivery to small intestine. These studies suggest that TMEM16A inhibitors can be drug candidates for conditions associated with accelerated gastric emptying such as dumping syndrome, as well as for improving oral glucose tolerance in diabetes mellitus and obesity, similar to the GLP-1 (glucagon-like peptide-1) agonists.

Figure 1. The effects of TMEM16A inhibition on gastrointestinal smooth muscle contractility and gut motility.

Figure 1.

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A. TMinh-23 treatment delays gastric emptying in mice assessed by [99mTc]-DTPA scintigraphy. B. TMinh-23 treatment improves glucose tolerance in mice after an oral glucose load. Adapted from Cil et al., 2019 with permission.

The differential contribution of TMEM16A in motility of stomach vs. intestine was also demonstrated in studies using earlier inhibitors and transgenic animals. Slow waves in mouse stomach tissue was shown to be 33-fold more sensitive than intestine to niflumic acid (Hwang et al., 2009). Similarly, CaCCinh-A01 and benzbromarone were shown to block gastric antral slow waves at much lower concentrations compared to intestinal slow waves in mouse tissues (Hwang et al., 2016). In inducible ICC-specific Tmem16a knockdown mice, gastric slow waves were abolished with reduced stomach emptying, however there were no obvious effects of Tmem16a knockdown on small intestinal slow waves (Hwang et al., 2019). Another study in inducible ICC-specific Tmem16a knockdown mice showed that in the intestine, partial loss of TMEM16A reduces duration of intestinal slow waves, whereas complete TMEM16A loss is required for slow wave abolishment (Malysz et al., 2017). These results collectively suggest the possibility of dose-dependent effects of TMEM16A in motility of different gastrointestinal segments and contribution of additional non-TMEM16A conductance pathways to pacemaker activity in small intestine. Overall, TMEM16A appears as a major determinant of gastric motility and emptying with potentially limited role in small intestinal motility of the mice. However, the exact mechanisms of this segment-specific effects of TMEM16A on gut motility and its relevance to human physiology remain to be elucidated.

In addition to its roles in stomach and small intestine, TMEM16A was also studied in colon. In mouse colon, TMEM16A in ICC was shown to be a key determinant of smooth muscle contractility (Drumm et al., 2019a, 2020b; Baker et al., 2025). TMEM16A is also involved in tonic inhibition of proximal colonic contractions which results in reduced Ca2+ release and TMEM16A conductance in ICC (Drumm et al., 2019b). A recent study showed that TMEM16A in ICC is critical for generation of colonic migrating motor complexes (CMMC) which can be blocked by TMEM16A inhibition and knockdown (Koh et al., 2022). In patients with slow-transit constipation, colonic TMEM16A expression was found to be reduced compared to healthy controls (Kashyap et al., 2011) suggesting a potential role for TMEM16A in clinical constipation. These studies collectively suggest key roles for TMEM16A in colonic motility, however future studies investigating relevance of these findings in human physiology and motility disorders (such as constipation) are warranted.

TMEM16A in anal sphincter contractility

TMEM16A is implicated in generation of internal anal sphincter tone, which is critical for fecal continence and defecation. TMEM16A deletion in anal sphincter smooth muscle cells or TMEM16A inhibition (by niflumic acid and T16Ainh-A01) was shown to reduce basal tone in the mouse internal anal sphincter (Zhang et al., 2016). Although this study demonstrated TMEM16A expression in both ICC and smooth muscle cells of internal anal sphincter, the contributions of ICC TMEM16A in anal sphincter tone was not specifically investigated. A recent study from another group similarly showed prominent TMEM16A expression in both smooth muscle cells and ICC of the mouse internal anal sphincter by immunostaining (Lu et al., 2024). Using cell-specific knockout models, the authors showed that TMEM16A in smooth muscle cells, but not in ICC, is critical for pacemaker activity and basal tone in the mouse internal anal sphincter. Although these studies suggested smooth muscle TMEM16A as the major determinant of anal sphincter tone in mice, other studies have challenged this. Using dual labeling and reporter mice, Cobine et al. showed that TMEM16A is expressed only in ICC but not smooth muscle cells of the mouse internal anal sphincter (Cobine et al., 2017). Using cell sorting, they similarly showed that TMEM16A gene expression in ICC is 26.5-fold higher than smooth muscle cells of the internal anal sphincter. Using a mouse model expressing a genetically-encoded Ca2+ sensor in ICC, a follow up study from the same group showed that mouse internal anal sphincter has two distinct subpopulations of ICC (Hannigan et al., 2020). They showed that type II cells, which constitute ~2/3 of the ICC population, have synchronous and global Ca2+ transients which were abolished by CaCCinh-A01 suggesting them as the candidate for slow wave and tone generation in the internal anal sphincter (Hannigan et al., 2020). Overall, these studies agreed regarding major contributions of TMEM16A in anal sphincter tone, although there is controversy regarding the cell type (ICC vs. smooth muscle) primarily responsible from the physiological effects. Future studies, including those in disease models and human tissues, can provide further insights regarding roles of TMEM16A in anal sphincter tone regulation. A recent study showed that TMEM16A is also expressed in ICC of lower esophageal sphincter of mouse and monkey, and TMEM16A inhibition by Ani9 reduces the tone in lower esophageal sphincter muscles (Drumm et al., 2022), which suggests potential contributions of TMEM16A in sphincter tone in gut and other tissues. These intriguing roles of TMEM16A in sphincter tone also warrant studying TMEM16A expression and activity in other sphincters of the gastrointestinal tract.

TMEM16A in cardiovascular system

In the vascular system, TMEM16A is expressed in the VSMC (Davis et al., 2010), endothelial cells (Ma et al., 2017) and pericytes (Heinze et al., 2014). TMEM16A activity in these cells is a major determinant of vascular tone and tissue perfusion. In contractile cells of the vasculature (VSMC and pericytes), active Cl− accumulation via anion transporters results in a more positive equilibrium potential for Cl− compared to the resting membrane potential. Agonist binding to Gq-coupled receptors elevates intracellular Ca2+, which activates TMEM16A channel causing membrane depolarization, activation of voltage-dependent Ca2+ channels, Ca2+ entry and contraction (Heinze et al., 2014; Korte et al., 2022). Although intracellular Cl− concentration varies in endothelial cells of different species and tissues, TMEM16A was also shown to mediate depolarization in endothelial cells of certain vascular beds (Suzuki et al., 2020). In this section, we discuss the recent advances on the roles of TMEM16A in VSMC including contributions of TMEM16A to vascular tone in different vascular beds which has potential therapeutic implications. In addition, we discuss recent intriguing findings on roles of endothelial and pericyte TMEM16A in vascular contractility and tissue perfusion.

TMEM16A in vascular smooth muscle cells

TMEM16A was originally identified as the major CaCC in pulmonary arterial smooth muscle cells (PASMC) (Manoury et al., 2010), which was followed by its identification in other human and rodent arteries (Sones et al., 2010; Thomas-Gatewood et al., 2011; Bulley et al., 2012; Ueda et al., 2022). Subsequent studies showed that TMEM16A inhibition (by T16Ainh-A01) induces relaxation in murine and human arteries (Davis et al., 2013), and TMEM16A knockout in VSMC decreases vascular contractions and blood pressure in mice (Heinze et al., 2014). A recent study investigated the effects of the potent inhibitor TMinh-23 on vascular contractility and blood pressure in rodents (Cil et al., 2021). In rat mesenteric resistance arteries, TMinh-23 treatment greatly reduced agonist-induced vasoconstriction responses (Cil et al., 2021), suggesting that TMEM16A is the major CaCC in this segment. Interestingly, TMinh-23 had greater vasodilator effect in the arteries of spontaneously hypertensive rats (SHR) compared to wildtypes (Fig. 2A), consistent with the previously reported greater TMEM16A expression in the vasculature of SHR compared to wildtypes (Wang et al., 2015; Askew Page et al., 2019). TMEM16A is also expressed in rat aorta and an earlier study showed that non-selective CaCC inhibitor niflumic acid reduces vasoconstriction in rat aortic rings (Criddle et al., 1996). However, the selective TMEM16A inhibitor TMinh-23 had minimal effects on aortic contractions in rats (Cil et al., 2021), which potentially suggest the presence of non-TMEM16A CaCCs in large arteries. Consistent with these in vitro results and earlier studies in knockout mice (Heinze et al., 2014), chronic TMinh-23 treatment had a sustained blood pressure reducing effect in SHR (Fig. 2B). Interestingly, TMinh-23 treatment had minimal effect on BP of wildtype rats or mice (Cil et al., 2021) in agreement with lower vasodilator efficacy of TMinh-23 in wildtype arteries. Overall, these studies suggest the major roles of TMEM16A in vascular contractility particularly in resistance arteries. These results also support the key physiological roles of TMEM16A in determining systemic vascular tone and blood pressure, and suggest that TMEM16A inhibition can be a novel treatment approach for hypertension (Fig. 3A and B).

Figure 2. The effects of TMEM16A inhibition on vascular contractility and blood pressure.

Figure 2.

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A. TMinh-23 effect on inhibition of U46619-induced contraction in mesenteric resistance arteries from spontaneously hypertensive rats (SHR) and wildtype (WT) rats. B. The effects of chronic (5-days) TMinh-23 treatment on systolic (SBP) and diastolic blood pressure (DBP) in SHR. Adapted from Cil et al., 2021 with permission.

Figure 3. Proposed mechanisms of the roles of TMEM16A in vascular contractility.

Figure 3.

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A. Agonists that elevate intracellular Ca2+ activate TMEM16A in vascular smooth muscle cells (VSMC). This results in depolarization that stimulates voltage-dependent Ca2+ channels (CaV), Ca2+ entry and contraction. B. TMEM16A inhibition prevents depolarization and contraction in VSMC. C. Binding of vasodilators (such as acetylcholine) to their receptors in endothelial cells results in TRPV4 activation, Ca2+ entry and subsequent TMEM16A activation. TMEM16A-mediated Cl− efflux reduces intracellular Cl− concentration, which stimulates WNK-OSR1 pathway and further activates TRPV4 and TMEM16A. This perpetual activation elevates intracellular Ca2+, activates K+ channels and leads to hyperpolarization which spreads to VSMC via gap junctions causing vasodilation. Created with BioRender.com

In addition to systemic hypertension, TMEM16A is also implicated in pulmonary hypertension (PH) which is characterized with increased pulmonary vascular tone. In animal models and patients with PH, PASMC are more depolarized with higher intracellular Ca2+ levels, which is thought to contribute to increased vascular reactivity and modeling in this setting (Leblanc et al., 2015). In rat models of PH, PASMC were found to have increased TMEM16A expression and CaCC currents with augmented pulmonary artery contractions which can be reversed by TMEM16A inhibitor T16Ainh-A01 (Sun et al., 2012; Forrest et al., 2012). A human study similarly showed that PASMC TMEM16A expression and CaCC currents are greatly increased in PH patients compared to healthy controls (Papp et al., 2019). The same study showed that TMEM16A knockdown or inhibition (by benzbromarone) can repolarize human PASMC and decrease proliferation. Although the results of this study are encouraging for potential efficacy of TMEM16A inhibitors in PH, there are some doubts about selectivity of the inhibitor since a recent study showed that benzbromarone has off-target effects on ryanodine receptors which seem to be responsible from its effects on smooth muscle contractility in the lung (Dwivedi et al., 2023). Although TMEM16A appears as a key determinant of pulmonary vascular tone and a promising target for PH, further studies with more selective inhibitors are warranted to determine roles of TMEM16A in pulmonary vascular physiology and diseases.

Recent studies provided novel insights on regulation and activation of TMEM16A in VSMC. In mouse PASMC, TMEM16A was shown to form a “super cluster” with IP3R and voltage-gated Ca2+ channels which appears to be critical for initiation and propagation of intracellular Ca2+ waves for agonist-induced pulmonary artery contraction (Akin et al., 2023). Activation of Gq-coupled GPCRs is a major mechanism that elevates intracellular Ca2+ and activates TMEM16A in VSMC. This pathway leads to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2), which was also proposed as a regulator of TMEM16A activity. An earlier study in rat PASMC showed that PIP2 is an inhibitor of TMEM16A currents (Pritchard et al., 2014). On the contrary, a subsequent study showed that a water-soluble PIP2 analog can activate TMEM16A in transfected HEK-293T cells and this effect is more pronounced at lower intracellular Ca2+ concentrations (Ta et al., 2017). Similarly, another study showed that PIP2 is a positive modulator of TMEM16A in heterologous expression systems (Le et al., 2019). These studies suggest the intriguing possibility of differential regulation of TMEM16A by PIP2 in different vascular beds, however the mechanisms and physiological significance of this phenomenon remain to be elucidated. Interactions with TRPC6 (transient receptor potential cation channel subfamily C member 6) cation channel was also proposed as an activation mechanism for TMEM16A. In rat cerebral artery myocytes, TMEM16A and TRPC6 was shown to localize in close proximity (Wang et al., 2016). The same study showed that the activation of TRPC6 stimulates Cl− currents in myocytes and vasoconstriction in cerebral arteries which can be reversed by TMEM16A inhibition (by T16Ainh-A01) and/or knockdown. These findings are consistent with an earlier study in rat cerebral artery myocytes, where cell swelling and pressure-induced membrane stretch (major activation mechanisms for TRPC6 (Spassova et al., 2006)) were shown to activate TMEM16A and contribute to pressure-induced vasoconstriction in rat cerebral arteries (Bulley et al., 2012). These studies suggests that local coupling of TRPC6 as an alternative activation mechanism for TMEM16A in cerebral vasculature. Future studies investigating interactions of TMEM16A with TRPC6 and other cation channels in different vascular beds might provide novel insights on activation and regulation of TMEM16A.

TMEM16A in endothelial cells

Although most of the earlier studies focused on TMEM16A in VSMC, recent studies demonstrated intriguing effects of endothelial TMEM16A on vascular contractility. TMEM16A knockdown in human and mouse endothelial cells was shown to greatly reduce CaCC currents suggesting TMEM16A is the major CaCC in endothelium (Ma et al., 2017). The same study also showed that endothelium-specific Tmem16a knockout in mice does not affect systolic blood pressure or acetylcholine-induced relaxation responses in aorta. However, in mice treated with angiotensin II, which upregulates TMEM16A expression and induces endothelial dysfunction, TMEM16A knockout in endothelial cells decreased systolic blood pressure and improved endothelium-dependent vasorelaxation via reduced reactive oxygen species generation (Ma et al., 2017). These findings suggested that endothelial TMEM16A might promote vasoconstriction and increase blood pressure in the setting of endothelial dysfunction, which appears consistent with its widely acknowledged vasoconstricting effects in VSMC. However, these findings were challenged by a recent study (Mata-Daboin et al., 2023) which showed that tamoxifen-inducible endothelial Tmem16a knockout mice have elevated diastolic blood pressure and decreased acetylcholine-induced relaxation in small mesenteric arteries compared to wildtypes. This study also demonstrated that acetylcholine stimulates Ca2+ entry via TRPV4 (transient receptor potential vanilloid 4) channel leading to TMEM16A activation and endothelial hyperpolarization which spreads to VSMC via gap junctions to induce vascular relaxation. Another recent study showed that endothelial TMEM16A activation reduces intracellular Cl− concentration which activates WNK-OSR1 (with no lysine kinases-oxidative stress-responsive kinase 1) pathway leading to increased TRPV4 activity and Ca2+ entry which demonstrates a novel mechanism for endothelial TMEM16A-mediated vasorelaxation response (Garrud et al., 2024). Although these studies provide novel insights on roles of endothelial TMEM16A in vascular contractility (Fig. 3C), including potential opposing effects of endothelial vs. VSMC TMEM16A on vascular tone, the effects of TMEM16A in VSMC seem to outweigh endothelial phenotype since in vivo studies showed profound blood pressure lowering effects of TMEM16A inhibitors (Cil et al., 2021). Future studies investigating contributions of VSMC vs. endothelial TMEM16A in disease models (such as hypertension) can be informative for elucidating the physiological significance of the cell-type specific effects of TMEM16A in the vasculature.

TMEM16A in pericytes

Pericytes are contractile cells that surround capillaries and control microvascular blood flow. TMEM16A is expressed in both human and rodent cerebral pericytes (Heinze et al., 2014; Korte et al., 2022). A recent study showed that TMEM16A activation is critical for pericyte contraction in mouse cerebral pericytes which stimulates capillary constriction after ischemia (Korte et al., 2022). The same study showed that, TMEM16A knockout in pericytes reduces endothelin 1-induced contraction in mouse cerebral pericytes and TMEM16A inhibitor Ani9 can reduce capillary constriction, improve cerebral blood flow and decrease infarct size in a mouse model of ischemic stroke. These findings are consistent with an earlier study which reported reduced infarct size and improved blood-brain-barrier integrity with non-selective CaCC inhibitor CaCCinh-A01 treatment in a mouse model of ischemic stroke (Liu et al., 2019). Interestingly, treatment with a TMEM16A inhibitor (T16Ainh-A01) had no effect on stroke severity in this earlier study. Overall, these findings suggest potential roles of TMEM16A in pericyte contraction and therapeutic utility of TMEM16A inhibitors in ischemic stroke where pericytes are a major treatment target. However, additional studies with selective TMEM16A inhibitors are warranted in clinically relevant models to validate TMEM16A as a target for vascular diseases mediated by pericytes. TMEM16A was also shown to be expressed in pericytes of retinal and skeletal muscle small vessels in mice (Heinze et al., 2014) and CaCC currents have been detected in pericytes of vasa recta in mouse kidney (Lin et al., 2010). It is plausible that pericyte TMEM16A may regulate microvascular circulation and blood flow in other organs which warrants further investigation.

Conclusions

Here we summarized the recent findings on roles of TMEM16A in gastrointestinal and vascular smooth muscle contractility. In the gut, TMEM16A activity is a key regulator of motility including stomach emptying and sphincter tone. In the cardiovascular system, TMEM16A is a major determinant of vascular tone, blood pressure and tissue perfusion. Altered TMEM16A expression and/or function might be contributing to development of certain gastrointestinal and cardiovascular diseases, for which TMEM16A is a potential therapeutic target. Although there have been concerns regarding selectivity of most experimental TMEM16A inhibitors, recent structural insights (Dinsdale et al., 2021) can be used to guide development of more selective compounds that can be used as research tools to better understand TMEM16A physiology.

Funding

This study was funded by grants from NIH (DK126070, EY036139) and Cystic Fibrosis Foundation (CIL24G0).

Footnotes

Competing interests

The authors declare that they have no financial or personal conflicts of interest related to the subject matter of this manuscript.

Data availability statement

No experiments or statistical analyses have been conducted, and no original data has been created for this review manuscript. All data used in this work are reproduced with permissions from the authors and journals with appropriate citations.

References

  1. Akin EJ, Aoun J, Jimenez C, Mayne K, Baeck J, Young MD, Sullivan B, Sanders KM, Ward SM, Bulley S, Jaggar JH, Earley S, Greenwood IA & Leblanc N (2023). ANO1, CaV1.2, and IP3R form a localized unit of EC-coupling in mouse pulmonary arterial smooth muscle. J Gen Physiol 155, e202213217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Al-Hosni R, Agostinelli E, Ilkan Z, Scofano L, Kaye R, Dinsdale RL, Acheson K, MacDonald A, Rivers D, Biosa A, Gunthorpe MJ, Platt F & Tammaro P (2025). Pharmacological profiling of small molecule modulators of the TMEM16A channel and their implications for the control of artery and capillary function. Br J Pharmacol 182, 1719–1740. [DOI] [PubMed] [Google Scholar]
  3. Al-Hosni R, Ilkan Z, Agostinelli E & Tammaro P (2022). The pharmacology of the TMEM16A channel: therapeutic opportunities. Trends Pharmacol Sci 43, 712–725. [DOI] [PubMed] [Google Scholar]
  4. Askew Page HR, Dalsgaard T, Baldwin SN, Jepps TA, Povstyan O, Olesen SP & Greenwood IA (2019). TMEM16A is implicated in the regulation of coronary flow and is altered in hypertension. Br J Pharmacol 176, 1635–1648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baker SA, Hwang SJ, Blair PJ, Sireika C, Wei L, Ro S, Ward SM & Sanders KM (2021). Ca2+ transients in ICC-MY define the basis for the dominance of the corpus in gastric pacemaking. Cell Calcium 99, 102472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Baker SA, Karwa M, Lee JY, Riar S, Drumm BT & Sanders KM (2025). Ca2+ signaling in myenteric interstitial cells of Cajal (ICC-MY) and their role as conditional pacemakers in the colon. Cell Calcium 125, 102990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Beckett EAH, Takeda Y, Yanase H, Sanders KM & Ward SM (2005). Synaptic specializations exist between enteric motor nerves and interstitial cells of Cajal in the murine stomach. J Comp Neurol 493, 193–206. [DOI] [PubMed] [Google Scholar]
  8. Boedtkjer DMB, Kim S, Jensen AB, Matchkov VM & Andersson KE (2015). New selective inhibitors of calcium-activated chloride channels - T16A(inh) -A01, CaCC(inh) -A01 and MONNA - what do they inhibit? Br J Pharmacol 172, 4158–4172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bulley S, Neeb ZP, Burris SK, Bannister JP, Thomas-Gatewood CM, Jangsangthong W & Jaggar JH (2012). TMEM16A/ANO1 channels contribute to the myogenic response in cerebral arteries. Circ Res 111, 1027–1036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O & Galietta LJV (2008). TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science 322, 590–594. [DOI] [PubMed] [Google Scholar]
  11. Chen H, Ordög T, Chen J, Young DL, Bardsley MR, Redelman D, Ward SM & Sanders KM (2007). Differential gene expression in functional classes of interstitial cells of Cajal in murine small intestine. Physiol Genomics 31, 492–509. [DOI] [PubMed] [Google Scholar]
  12. Cil O, Anderson MO, Yen R, Kelleher B, Huynh TL, Seo Y, Nilsen SP, Turner JR & Verkman AS (2019). Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A. FASEB J 33, 11247–11257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cil O, Chen X, Askew Page HR, Baldwin SN, Jordan MC, Myat Thwe P, Anderson MO, Haggie PM, Greenwood IA, Roos KP & Verkman AS (2021). A small molecule inhibitor of the chloride channel TMEM16A blocks vascular smooth muscle contraction and lowers blood pressure in spontaneously hypertensive rats. Kidney Int 100, 311–320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cobine CA, Hannah EE, Zhu MH, Lyle HE, Rock JR, Sanders KM, Ward SM & Keef KD (2017). ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter. J Physiol 595, 2021–2041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Criddle DN, de Moura RS, Greenwood IA & Large WA (1996). Effect of niflumic acid on noradrenaline-induced contractions of the rat aorta. Br J Pharmacol 118, 1065–1071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Davis AJ, Forrest AS, Jepps TA, Valencik ML, Wiwchar M, Singer CA, Sones WR, Greenwood IA & Leblanc N (2010). Expression profile and protein translation of TMEM16A in murine smooth muscle. Am J Physiol Cell Physiol 299, C948–959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Davis AJ, Shi J, Pritchard HAT, Chadha PS, Leblanc N, Vasilikostas G, Yao Z, Verkman AS, Albert AP & Greenwood IA (2013). Potent vasorelaxant activity of the TMEM16A inhibitor T16A(inh) -A01. Br J Pharmacol 168, 773–784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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, 758–768. [DOI] [PubMed] [Google Scholar]
  19. Dinsdale RL, Pipatpolkai T, Agostinelli E, Russell AJ, Stansfeld PJ & Tammaro P (2021). An outer-pore gate modulates the pharmacology of the TMEM16A channel. Proc Natl Acad Sci U S A 118, e2023572118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Drumm BT, Hannigan KI, Lee JY, Rembetski BE, Baker SA, Koh SD, Cobine CA & Sanders KM (2022). Ca2+ signalling in interstitial cells of Cajal contributes to generation and maintenance of tone in mouse and monkey lower oesophageal sphincters. J Physiol 600, 2613–2636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Drumm BT, Hennig GW, Battersby MJ, Cunningham EK, Sung TS, Ward SM, Sanders KM & Baker SA (2017). Clustering of Ca2+ transients in interstitial cells of Cajal defines slow wave duration. J Gen Physiol 149, 703–725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Drumm BT, Hwang SJ, Baker SA, Ward SM & Sanders KM (2019a). Ca2+ signalling behaviours of intramuscular interstitial cells of Cajal in the murine colon. J Physiol 597, 3587–3617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Drumm BT, Rembetski BE, Baker SA & Sanders KM (2019b). Tonic inhibition of murine proximal colon is due to nitrergic suppression of Ca2+ signaling in interstitial cells of Cajal. Sci Rep 9, 4402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Drumm BT, Rembetski BE, Huynh K, Nizar A, Baker SA & Sanders KM (2020a). Excitatory cholinergic responses in mouse colon intramuscular interstitial cells of Cajal are due to enhanced Ca2+ release via M3 receptor activation. FASEB J 34, 10073–10095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Drumm BT, Rembetski BE, Messersmith K, Manierka MS, Baker SA & Sanders KM (2020b). Pacemaker function and neural responsiveness of subserosal interstitial cells of Cajal in the mouse colon. J Physiol 598, 651–681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Dwivedi R, Drumm BT, Alkawadri T, Martin SL, Sergeant GP, Hollywood MA & Thornbury KD (2023). The TMEM16A blockers benzbromarone and MONNA cause intracellular Ca2+-release in mouse bronchial smooth muscle cells. Eur J Pharmacol 947, 175677. [DOI] [PubMed] [Google Scholar]
  27. Forrest AS, Joyce TC, Huebner ML, Ayon RJ, Wiwchar M, Joyce J, Freitas N, Davis AJ, Ye L, Duan DD, Singer CA, Valencik ML, Greenwood IA & Leblanc N (2012). Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension. Am J Physiol Cell Physiol 303, C1229–1243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Garrud TAC, Bell B, Mata-Daboin A, Peixoto-Neves D, Collier DM, Cordero-Morales JF & Jaggar JH (2024). WNK kinase is a vasoactive chloride sensor in endothelial cells. Proc Natl Acad Sci U S A 121, e2322135121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Genovese M, Buccirossi M, Guidone D, De Cegli R, Sarnataro S, di Bernardo D & Galietta LJV (2023). Analysis of inhibitors of the anoctamin-1 chloride channel (transmembrane member 16A, TMEM16A) reveals indirect mechanisms involving alterations in calcium signalling. Br J Pharmacol 180, 775–785. [DOI] [PubMed] [Google Scholar]
  30. Gomez-Pinilla PJ, Gibbons SJ, Bardsley MR, Lorincz A, Pozo MJ, Pasricha PJ, Van de Rijn M, West RB, Sarr MG, Kendrick ML, Cima RR, Dozois EJ, Larson DW, Ordog T & Farrugia G (2009). Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 296, G1370–1381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hannigan KI, Bossey AP, Foulkes HJL, Drumm BT, Baker SA, Ward SM, Sanders KM, Keef KD & Cobine CA (2020). A novel intramuscular Interstitial Cell of Cajal is a candidate for generating pacemaker activity in the mouse internal anal sphincter. Sci Rep 10, 10378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Heinze C, Seniuk A, Sokolov MV, Huebner AK, Klementowicz AE, Szijártó IA, Schleifenbaum J, Vitzthum H, Gollasch M, Ehmke H, Schroeder BC & Hübner CA (2014). Disruption of vascular Ca2+-activated chloride currents lowers blood pressure. J Clin Invest 124, 675–686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Horiguchi K, Sanders KM & Ward SM (2003). Enteric motor neurons form synaptic-like junctions with interstitial cells of Cajal in the canine gastric antrum. Cell Tissue Res 311, 299–313. [DOI] [PubMed] [Google Scholar]
  34. Huang F, Rock JR, Harfe BD, Cheng T, Huang X, Jan YN & Jan LY (2009). Studies on expression and function of the TMEM16A calcium-activated chloride channel. Proc Natl Acad Sci U S A 106, 21413–21418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Hwang SJ, Basma N, Sanders KM & Ward SM (2016). Effects of new-generation inhibitors of the calcium-activated chloride channel anoctamin 1 on slow waves in the gastrointestinal tract. Br J Pharmacol 173, 1339–1349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hwang SJ, Blair PJA, Britton FC, O’Driscoll KE, Hennig G, Bayguinov YR, Rock JR, Harfe BD, Sanders KM & Ward SM (2009). Expression of anoctamin 1/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles. J Physiol 587, 4887–4904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Hwang SJ, Pardo DM, Zheng H, Bayguinov Y, Blair PJ, Fortune-Grant R, Cook RS, Hennig GW, Shonnard MC, Grainger N, Peri LE, Verma SD, Rock J, Sanders KM & Ward SM (2019). Differential sensitivity of gastric and small intestinal muscles to inducible knockdown of anoctamin 1 and the effects on gastrointestinal motility. J Physiol 597, 2337–2360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kashyap P, Gomez-Pinilla PJ, Pozo MJ, Cima RR, Dozois EJ, Larson DW, Ordog T, Gibbons SJ & Farrugia G (2011). Immunoreactivity for Ano1 detects depletion of Kit-positive interstitial cells of Cajal in patients with slow transit constipation. Neurogastroenterol Motil 23, 760–765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Klein S, Seidler B, Kettenberger A, Sibaev A, Rohn M, Feil R, Allescher H-D, Vanderwinden J-M, Hofmann F, Schemann M, Rad R, Storr MA, Schmid RM, Schneider G & Saur D (2013). Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity. Nat Commun 4, 1630. [DOI] [PubMed] [Google Scholar]
  40. Koh SD, Drumm BT, Lu H, Kim HJ, Ryoo S-B, Kim H-U, Lee JY, Rhee P-L, Wang Q, Gould TW, Heredia D, Perrino BA, Hwang SJ, Ward SM & Sanders KM (2022). Propulsive colonic contractions are mediated by inhibition-driven poststimulus responses that originate in interstitial cells of Cajal. Proc Natl Acad Sci U S A 119, e2123020119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Korte N, Ilkan Z, Pearson CL, Pfeiffer T, Singhal P, Rock JR, Sethi H, Gill D, Attwell D & Tammaro P (2022). The Ca2+-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia. J Clin Invest 132, e154118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Le SC, Jia Z, Chen J & Yang H (2019). Molecular basis of PIP2-dependent regulation of the Ca2+-activated chloride channel TMEM16A. Nat Commun 10, 3769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Leblanc N, Forrest AS, Ayon RJ, Wiwchar M, Angermann JE, Pritchard HAT, Singer CA, Valencik ML, Britton F & Greenwood IA (2015). Molecular and functional significance of Ca(2+)-activated Cl(−) channels in pulmonary arterial smooth muscle. Pulm Circ 5, 244–268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Lin H, Pallone TL & Cao C (2010). Murine vasa recta pericyte chloride conductance is controlled by calcium, depolarization, and kinase activity. Am J Physiol Regul Integr Comp Physiol 299, R1317–1325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Liu P-Y, Zhang Z, Liu Y, Tang X-L, Shu S, Bao X-Y, Zhang Y, Gu Y, Xu Y & Cao X (2019). TMEM16A Inhibition Preserves Blood-Brain Barrier Integrity After Ischemic Stroke. Front Cell Neurosci 13, 360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Lu P, Lifshitz LM, Bellve K & ZhuGe R (2024). TMEM16A in smooth muscle cells acts as a pacemaker channel in the internal anal sphincter. Commun Biol 7, 151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Ma M-M, Gao M, Guo K-M, Wang M, Li X-Y, Zeng X-L, Sun L, Lv X-F, Du Y-H, Wang G-L, Zhou J-G & Guan Y-Y (2017). TMEM16A Contributes to Endothelial Dysfunction by Facilitating Nox2 NADPH Oxidase-Derived Reactive Oxygen Species Generation in Hypertension. Hypertension 69, 892–901. [DOI] [PubMed] [Google Scholar]
  48. Malysz J, Gibbons SJ, Saravanaperumal SA, Du P, Eisenman ST, Cao C, Oh U, Saur D, Klein S, Ordog T & Farrugia G (2017). Conditional genetic deletion of Ano1 in interstitial cells of Cajal impairs Ca2+ transients and slow waves in adult mouse small intestine. Am J Physiol Gastrointest Liver Physiol 312, G228–G245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Manoury B, Tamuleviciute A & Tammaro P (2010). TMEM16A/anoctamin 1 protein mediates calcium-activated chloride currents in pulmonary arterial smooth muscle cells. J Physiol 588, 2305–2314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Mata-Daboin A, Garrud TAC, Fernandez-Pena C, Peixoto-Neves D, Leo MD, Bernardelli AK, Singh P, Malik KU & Jaggar JH (2023). Vasodilators activate the anion channel TMEM16A in endothelial cells to reduce blood pressure. Sci Signal 16, eadh9399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Namkung W, Phuan P-W & 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, 2365–2374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Papp R et al. (2019). Targeting TMEM16A to reverse vasoconstriction and remodelling in idiopathic pulmonary arterial hypertension. Eur Respir J 53, 1800965. [DOI] [PubMed] [Google Scholar]
  53. Pritchard H a. T, Leblanc N, Albert AP & Greenwood IA (2014). Inhibitory role of phosphatidylinositol 4,5-bisphosphate on TMEM16A-encoded calcium-activated chloride channels in rat pulmonary artery. Br J Pharmacol 171, 4311–4321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Schroeder BC, Cheng T, Jan YN & Jan LY (2008). Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell 134, 1019–1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Seo Y, Lee HK, Park J, Jeon D-K, Jo S, Jo M & Namkung W (2016). Ani9, A Novel Potent Small-Molecule ANO1 Inhibitor with Negligible Effect on ANO2. PLoS One 11, e0155771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Singh RD, Gibbons SJ, Saravanaperumal SA, Du P, Hennig GW, Eisenman ST, Mazzone A, Hayashi Y, Cao C, Stoltz GJ, Ordog T, Rock JR, Harfe BD, Szurszewski JH & Farrugia G (2014). Ano1, a Ca2+-activated Cl- channel, coordinates contractility in mouse intestine by Ca2+ transient coordination between interstitial cells of Cajal. J Physiol 592, 4051–4068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Sones WR, Davis AJ, Leblanc N & Greenwood IA (2010). Cholesterol depletion alters amplitude and pharmacology of vascular calcium-activated chloride channels. Cardiovasc Res 87, 476–484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Spassova MA, Hewavitharana T, Xu W, Soboloff J & Gill DL (2006). A common mechanism underlies stretch activation and receptor activation of TRPC6 channels. Proc Natl Acad Sci U S A 103, 16586–16591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Sun H, Xia Y, Paudel O, Yang X-R & Sham JSK (2012). Chronic hypoxia-induced upregulation of Ca2+-activated Cl- channel in pulmonary arterial myocytes: a mechanism contributing to enhanced vasoreactivity. J Physiol 590, 3507–3521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Sung TS, Hwang SJ, Koh SD, Bayguinov Y, Peri LE, Blair PJ, Webb TI, Pardo DM, Rock JR, Sanders KM & Ward SM (2018). The cells and conductance mediating cholinergic neurotransmission in the murine proximal stomach. J Physiol 596, 1549–1574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Suzuki T, Yasumoto M, Suzuki Y, Asai K, Imaizumi Y & Yamamura H (2020). TMEM16A Ca2+-Activated Cl- Channel Regulates the Proliferation and Migration of Brain Capillary Endothelial Cells. Mol Pharmacol 98, 61–71. [DOI] [PubMed] [Google Scholar]
  62. Ta CM, Acheson KE, Rorsman NJG, Jongkind RC & Tammaro P (2017). Contrasting effects of phosphatidylinositol 4,5-bisphosphate on cloned TMEM16A and TMEM16B channels. Br J Pharmacol 174, 2984–2999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Thomas-Gatewood C, Neeb ZP, Bulley S, Adebiyi A, Bannister JP, Leo MD & Jaggar JH (2011). TMEM16A channels generate Ca2+-activated Cl− currents in cerebral artery smooth muscle cells. Am J Physiol Heart Circ Physiol 301, H1819–1827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Truong EC, Phuan PW, Reggi AL, Ferrera L, Galietta LJV, Levy SE, Moises AC, Cil O, Diez-Cecilia E, Lee S, Verkman AS & Anderson MO (2017). Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A). J Med Chem 60, 4626–4635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Ueda S, Manabe Y, Kubo N, Morino N, Yuasa H, Shiotsu M, Tsuji T, Sugawara T & Kambe T (2022). Early secretory pathway-resident Zn transporter proteins contribute to cellular sphingolipid metabolism through activation of sphingomyelin phosphodiesterase 1. Am J Physiol Cell Physiol 322, C948–C959. [DOI] [PubMed] [Google Scholar]
  66. Wang B, Li C, Huai R & Qu Z (2015). Overexpression of ANO1/TMEM16A, an arterial Ca2+-activated Cl- channel, contributes to spontaneous hypertension. J Mol Cell Cardiol 82, 22–32. [DOI] [PubMed] [Google Scholar]
  67. Wang Q, Leo MD, Narayanan D, Kuruvilla KP & Jaggar JH (2016). Local coupling of TRPC6 to ANO1/TMEM16A channels in smooth muscle cells amplifies vasoconstriction in cerebral arteries. Am J Physiol Cell Physiol 310, C1001–1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim W-S, Park SP, Lee J, Lee B, Kim B-M, Raouf R, Shin YK & Oh U (2008). TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature 455, 1210–1215. [DOI] [PubMed] [Google Scholar]
  69. Zhang C-H et al. (2016). The molecular basis of the genesis of basal tone in internal anal sphincter. Nat Commun 7, 11358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Zhu MH, Kim TW, Ro S, Yan W, Ward SM, Koh SD & Sanders KM (2009). A Ca(2+)-activated Cl(−) conductance in interstitial cells of Cajal linked to slow wave currents and pacemaker activity. J Physiol 587, 4905–4918. [DOI] [PMC free article] [PubMed] [Google Scholar]

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