The bestrophin- and TMEM16A-associated Ca ²⁺-activated Cl ^– channels in vascular smooth muscles

Abstract

The presence of Ca ²⁺-activated Cl ^– currents ( I _Cl(Ca) ) in vascular smooth muscle cells (VSMCs) is well established. I _Cl(Ca) are supposedly important for arterial contraction by linking changes in [Ca ²⁺] _i and membrane depolarization. Bestrophins and some members of the TMEM16 protein family were recently associated with I _Cl(Ca) . Two distinct I _Cl(Ca) are characterized in VSMCs; the cGMP-dependent I _Cl(Ca) dependent upon bestrophin expression and the ‘classical’ Ca ²⁺-activated Cl ^– current, which is bestrophin-independent. Interestingly, TMEM16A is essential for both the cGMP-dependent and the classical I _Cl(Ca) . Furthermore, TMEM16A has a role in arterial contraction while bestrophins do not. TMEM16A’s role in the contractile response cannot be explained however only by a simple suppression of the depolarization by Cl ^– channels. It is suggested that TMEM16A expression modulates voltage-gated Ca ²⁺ influx in a voltage-independent manner and recent studies also demonstrate a complex role of TMEM16A in modulating other membrane proteins.