Ca2+-activated Cl− channels at a glance

Berg, Jim; Yang, Huanghe; Jan, Yuh Nung

doi:10.1242/jcs.093260

Cited by 67 publications

(48 citation statements)

References 64 publications

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“…88,89 In 2008, three groups of investigators independently showed that two members of the TMEM16 gene family, TMEM16A and TMEM16B, or anoctamin-1 and anoctamin-2 (ANO1, ANO2), encoded for CaCCs. 8 -dependent phospholipid scramblase activity. 94 Importantly, the biophysical properties and pharmacology of expressed ANO1 and ANO2 are very similar to those of CaCC currents recorded from native cells: (1) activation by physiological levels of intracellular Ca 2+ (∼200-1,000 nM), (2) Anoctamins are predicted to exhibit 8 transmembrane domains with both N-and C-termini facing the cytoplasm (Fig.…”

Section: Regulation Of Caccs In Vascular Myocytesmentioning

confidence: 99%

Molecular and Functional Significance of Ca²⁺‐Activated Cl⁻ Channels in Pulmonary Arterial Smooth Muscle

et al. 2015

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Increased peripheral resistance of small distal pulmonary arteries is a hallmark signature of pulmonary hypertension (PH) and is believed to be the consequence of enhanced vasoconstriction to agonists, thickening of the arterial wall due to remodeling, and increased thrombosis. The elevation in arterial tone in PH is attributable, at least in part, to smooth muscle cells of PH patients being more depolarized and displaying higher intracellular Ca 2+ levels than cells from normal subjects. It is now clear that downregulation of voltage-dependent K + channels (e.g., Kv1.5) and increased expression and activity of voltage-dependent (Cav1.2) and voltage-independent (e.g., canonical and vanilloid transient receptor potential [TRPC and TRPV]) Ca 2+ channels play an important role in the functional remodeling of pulmonary arteries in PH. This review focuses on an anion-permeable channel that is now considered a novel excitatory mechanism in the systemic and pulmonary circulations. It is permeable to Cl − and is activated by a rise in intracellular Ca 2+ concentration (Ca 2+-activated Cl − channel, or CaCC). The first section outlines the biophysical and pharmacological properties of the channel and ends with a description of the molecular candidate genes postulated to encode for CaCCs, with particular emphasis on the bestrophin and the newly discovered TMEM16 and anoctamin families of genes. The second section provides a review of the various sources of Ca 2+ activating CaCCs, which include stimulation by mobilization from intracellular Ca 2+ stores and Ca 2+ entry through voltage-dependent and voltage-independent Ca 2+ channels. The third and final section summarizes recent findings that suggest a potentially important role for CaCCs and the gene TMEM16A in PH.Keywords: calcium-activated chloride channels, pulmonary hypertension, TMEM16A, anoctamin, bestrophin. . They are widely distributed small-conductance channels located in the plasma membrane of many cell types and are hypothesized to serve important functions in sperm maturation, fluid transport across epithelial tissues, cardiac repolarization, olfactory transduction, photoreceptor stimulation, neuronal and skeletal muscle excitation, cardiac repolarization, and vascular smooth muscle excitability and contraction. For more information on the general properties and role of CaCCs in various cell types and tissues, the reader is invited to consult excellent reviews on this topic. [1][2][3][4][5][6][7][8][9][10][11] Byrne and Large 12 were the first to report the existence of a Ca 2+ -activated Cl − conductance in smooth muscle by describing its general properties in rat anococcygeus smooth muscle. Since this initial discovery, that group and others have described this conductance in a variety of smooth muscle cells, including vascular smooth muscle cells (VSMCs). 1,4,7 The identification in 2008 by three independent groups of the TMEM16, or anoctamin, family of genes as novel candidates for CaCCs 13-15 sparked a renewed interest in refining our understan...

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Section: Regulation Of Caccs In Vascular Myocytesmentioning

confidence: 99%

Molecular and Functional Significance of Ca²⁺‐Activated Cl⁻ Channels in Pulmonary Arterial Smooth Muscle

et al. 2015

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“…Later they have been observed in diverse tissues including exocrine gland cells, neurons, heart, skeletal and smooth muscle [3][4][5][6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 97%

Multiple effects of anthracene-9-carboxylic acid on the TMEM16B/anoctamin2 calcium-activated chloride channel

Cherian

Menini

Boccaccio

2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Ca(2+)-activated Cl(-) currents (CaCCs) play important roles in many physiological processes. Recent studies have shown that TMEM16A/anoctamin1 and TMEM16B/anoctamin2 constitute CaCCs in several cell types. Here we have investigated for the first time the extracellular effects of the Cl(-) channel blocker anthracene-9-carboxylic acid (A9C) and of its non-charged analogue anthracene-9-methanol (A9M) on TMEM16B expressed in HEK 293T cells, using the whole-cell patch-clamp technique. A9C caused a voltage-dependent block of outward currents and inhibited a larger fraction of the current as depolarization increased, whereas the non-charged A9M produced a small, not voltage dependent block of outward currents. A similar voltage-dependent block by A9C was measured both when TMEM16B was activated by 1.5 and 13μM Ca(2+). However, in the presence of 1.5μM Ca(2+) (but not in 13μM Ca(2+)), A9C also induced a strong potentiation of tail currents measured at -100mV after depolarizing voltages, as well as a prolongation of the deactivation kinetics. On the contrary, A9M did not produce potentiation of tail currents, showing that the negative charge is required for potentiation. Our results provide the first evidence that A9C has multiple effects on TMEM16B and that the negative charge of A9C is necessary both for voltage-dependent block and for potentiation. Future studies are required to identify the molecular mechanisms underlying these complex effects of A9C on TMEM16B. Understanding these mechanisms will contribute to the elucidation of the structure and functional properties of TMEM16B channels.

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“…However, several studies on many ion channels have described interactions between permeation and gating, suggesting that these two processes are not always independent (Hille, 2001). Ca 2+ -activated Cl  channels (CaCCs) play important physiological functions, including regulation of cell excitability, fluid secretion, and smooth muscle contraction and block of polyspermy in some oocytes (Frings et al, 2000;Hartzell et al, 2005;Leblanc et al, 2005;Petersen, 2005;Wray et al, 2005;Lalonde et al, 2008;Duran et al, 2010;Berg et al, 2012;Huang et al, 2012a). Evidence that anions modify gating of endogenous CaCCs was reported in several cell types.…”

Section: Introductionmentioning

confidence: 99%

Interactions between permeation and gating in the TMEM16B/anoctamin2 calcium-activated chloride channel

Betto¹,

Cherian²,

Pifferi³

et al. 2014

Journal of General Physiology

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Ca2+-activated Cl− channels at a glance

Cited by 67 publications

References 64 publications

Molecular and Functional Significance of Ca²⁺‐Activated Cl⁻ Channels in Pulmonary Arterial Smooth Muscle

Molecular and Functional Significance of Ca²⁺‐Activated Cl⁻ Channels in Pulmonary Arterial Smooth Muscle

Multiple effects of anthracene-9-carboxylic acid on the TMEM16B/anoctamin2 calcium-activated chloride channel

Interactions between permeation and gating in the TMEM16B/anoctamin2 calcium-activated chloride channel

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Ca2+-activated Cl− channels at a glance

Cited by 67 publications

References 64 publications

Molecular and Functional Significance of Ca2+‐Activated Cl− Channels in Pulmonary Arterial Smooth Muscle

Molecular and Functional Significance of Ca2+‐Activated Cl− Channels in Pulmonary Arterial Smooth Muscle

Multiple effects of anthracene-9-carboxylic acid on the TMEM16B/anoctamin2 calcium-activated chloride channel

Interactions between permeation and gating in the TMEM16B/anoctamin2 calcium-activated chloride channel

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Molecular and Functional Significance of Ca²⁺‐Activated Cl⁻ Channels in Pulmonary Arterial Smooth Muscle

Molecular and Functional Significance of Ca²⁺‐Activated Cl⁻ Channels in Pulmonary Arterial Smooth Muscle