Autism associated mutations in β₂ subunit of voltage-gated calcium channels constitutively activate gene expression

Membrane depolarization triggers gene expression through voltage-gated calcium channels (VGCC) in a process called Excitation-transcription (ET) coupling. Mutations in the channel subunits α₁1.2, or β_2d, are associated with neurodevelopmental disorders such as ASD. Here, we found that two mutations S143F and G113S within the rat Cavβ_2a corresponding to autistic related mutations Cavβ_2d^S197F and Cavβ_2d^G167S in the human Cavβ_2d, activate ET-coupling via the RAS/ERK/CREB pathway. Membrane depolarization of HEK293 cells co-expressing α₁1.2 and α_2δ with Cavβ_2a^S143F or Cavβ_2a^G113S triggers constitutive transcriptional activation, which is correlated with facilitated channel activity. Similar to the Timothy-associated autistic mutation α₁1.2^G406R, constitutive gene activation is attributed to a hyperpolarizing shift in the activation kinetics of Cav1.2. Pulldown of RasGRF2 and RhoGEF by wt and the Cavβ_2a autistic mutants is consistent with Cavβ₂/Ras activation in ET coupling and implicates Rho signaling as yet another molecular pathway activated by Cavα₁1.2/Cavβ2. Facilitated spontaneous channel activity preceding enhanced gene activation via the Ras/ERK/CREB pathway, appears a general molecular mechanism for Ca²⁺ channel mediated ASD and other neurodevelopmental disorders.