Inhibitory effects on L- and N-type calcium channels by a novel Ca V β 1 variant identified in a patient with autism spectrum disorder.

Voltage-gated calcium channel (VGCC) subunits have been genetically associated with autism spectrum disorders (ASD). The properties of the pore-forming VGCC subunit are modulated by auxiliary β-subunits, which exist in four isoforms (Ca V β 1-4 ). Our previous findings suggested that activation of L-type VGCCs is a common feature of Ca V β 2 subunit mutations found in ASD patients. In the current study, we functionally characterized a novel Ca V β 1b variant (p.R296C) identified in an ASD patient. We used whole-cell and single-channel patch clamp to study the effect of Ca V β 1b_R296C on the function of L- and N-type VGCCs. Furthermore, we used co-immunoprecipitation followed by Western blot to evaluate the interaction of the Ca V β 1b -subunits with the RGK-protein Gem. Our data obtained at both, whole-cell and single-channel levels, show that compared to a wild-type Ca V β 1b , the Ca V β 1b_R296C variant inhibits L- and N-type VGCCs. Interaction with and modulation by the RGK-protein Gem seems to be intact. Our findings indicate functional effects of the Ca V β 1b_R296C variant differing from that attributed to Ca V β 2 variants found in ASD patients. Further studies have to detail the effects on different VGCC subtypes and on VGCC expression.