Functional properties of the Cav1.2 calcium channel activated by calmodulin in the absence of α₂δ subunits

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) rendered active α1C/Cavβ channel in the absence of α2δ. Coexpression of CaMex with α1C and β2d in calcium-channel-free COS-1 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 approximately 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.