Cl− channels in smooth muscle cells

Abstract

In smooth muscle cells (SMCs), the intracellular chloride ion (Cl−) concentration is high due to accumulation by Cl−/HCO3− exchange and Na+, K+, Cl− cotransportation. The equilibrium potential for Cl− (ECl) is more positive than physiological membrane potentials (Em), with Cl− efflux inducing membrane depolarization. Early studies used electrophysiology and non-specific antagonists to study the physiological relevance of Cl− channels in SMCs. More recent reports have incorporated molecular biological approaches to identify and determine the functional significance of several different Cl− channels. Both “classic” and cGMP-dependent calcium (Ca2+)-activated (ClCa) channels and volume-sensitive Cl− channels are present, with TMEM16A/ANO1, bestrophins and ClC-3, respectively, proposed as molecular candidates for these channels. The cystic fibrosis transmembrane conductance regulator (CFTR) has also been described in SMCs. This review will focus on discussing recent progress made in identifying each of these Cl− channels in SMCs, their physiological functions, and contribution to diseases that modify contraction, apoptosis and cell proliferation.

Activation of Ca2+‐activated Cl− channel ANO1 by localized Ca2+ signals

“…There are a number of Cl − channels expressed in smooth muscle cells (reviewed in Bulley & Jaggar, 2014) and there are at least two types of CaCCs, a ‘classical’ CaCC that displays voltage‐dependent gating and is likely to be mediated by ANO1 (Manoury et al . 2010; Thomas‐Gatewood et al .…”

“…2004, 2005), which possibly depends on bestrophins (Matchkov et al . 2008; Bulley & Jaggar, 2014). Several excellent recent reviews discuss the roles and regulation of CaCCs in smooth muscles (Sanders et al .…”

“…2012; Matchkov et al . 2013; Bulley & Jaggar, 2014); therefore, here we will briefly consider only the information concerning the activation of ANO1‐mediated CaCCs by localized Ca 2+ signalling.…”

“…2002; Bulley & Jaggar, 2014). Accordingly, CaCC activation in smooth muscles induces depolarization and vasoconstriction.…”

“…2012) have been reported (reviewed in Leblanc et al . 2005; Bulley & Jaggar, 2014). However, physiological activation of ANO1‐mediated CaCCs in smooth muscle is likely to depend on co‐localized Ca 2+ signals since Ca 2+ sensitivity of ANO1 at physiologically relevant voltages is lower than the physiological range of global [Ca 2+ ] i in smooth muscle cells (Knot & Nelson, 1998; Bulley et al .…”