Inhibitory effects on L- and N-type calcium channels by a novel Ca-V beta(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 beta-subunits, which exist in four isoforms (Ca-V beta(1-4)). Our previous findings suggested that activation of L-type VGCCs is a common feature of Ca-V beta(2) subunit mutations found in ASD patients. In the current study, we functionally characterized a novel Ca-V beta(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 beta(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 beta(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 beta(1b), the Ca-V beta(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 beta(1b_R296C) variant differing from that attributed to Ca-V beta(2) variants found in ASD patients. Further studies have to detail the effects on different VGCC subtypes and on VGCC expression.

Automated summary

In this study, we characterized a novel variant of Ca-V beta(1b) identified in an ASD patient. Our results showed that this variant inhibits the function of L- and N-type VGCCs, but maintains its interaction with and modulation by the RGK-protein Gem. Our findings suggest functional effects of this Ca-V beta(1b_R296C) variant different from the Ca-V beta(2) variants found in ASD patients.