Inhibitory effects on L- and N-type calcium channels by a novel Ca_Vβ₁ variant identified in a patient with autism...

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_Vβ_1-4). Our previous findings suggested that activation of L-type VGCCs is a common feature of Ca_Vβ₂ subunit mutations found in ASD patients. In the current study, we functionally characterized a novel Ca_Vβ_1b variant (p.R296C) identified in an ASD patient. We used whole-cell and single-channel patch clamp to study the effect of Ca_Vβ_{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_Vβ_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_Vβ_1b, the Ca_Vβ_{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_Vβ_{1b_R296C} variant differing from that attributed to Ca_Vβ₂ variants found in ASD patients. Further studies have to detail the effects on different VGCC subtypes and on VGCC expression.