The bestrophin- and TMEM16A-associated Ca2+-activated Cl- channels in vascular smooth muscles

The presence of Ca2+-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 [Ca2+](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' Ca2+-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 Ca2+ influx in a voltage-independent manner and recent studies also demonstrate a complex role of TMEM16A in modulating other membrane proteins.