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.