Functional Properties Of The CaV1.2 Calcium Channel Activated By Calmodulin In The Absence Of α2δ Subunits

Abstract

Voltage-activated Cav1.2 calcium channels require association of the pore-forming α1C subunit with accessory Cavβ and α2δ subunits. Binding of a single calmodulin (CaM) to α1C supports Ca2+-dependent inactivation (CDI). The human Cav1.2 channel is silent in the absence of Cavβ and/or α2δ. Recently, we found that coexpression of exogenous CaM (CaMex) supports plasma-membrane targeting, gating facilitation and CDI of the channel in the absence of Cavβ. Here we discovered that CaMex and its Ca2+-insensitive mutant (CaM1234) activate the α1C/Cavβ channel in the absence of α2δ. Coexpression of CaMex with α1C and β2d in calcium-channel-free COS1 cells recovered gating of the channel and supported CDI. Voltage-dependence of activation was shifted by ≈ +40 mV to depolarization potentials. The calcium current reached maximum at +40 mV (20 mM Ca2+) and exhibited ≈3 times slower activation and 5 times slower inactivation kinetics compared to the wild-type channel. Furthermore, both CaMex and CaM1234 accelerated recovery from inactivation and induced facilitation of the calcium current by strong depolarization prepulse, the properties absent from the human vascular/neuronal Cav1.2 channel. The data suggest a previously unknown action of CaM that in the presence of Cavβ translates into activation of the α2δ-deficient calcium channel and alteration of its properties.