Autism associated mutations in β 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 α1.2, or β, are associated with neurodevelopmental disorders such as ASD. Here, we found that two mutations S143F and G113S within the rat Cavβ corresponding to autistic related mutations Cavβ and Cavβ in the human Cavβ, activate ET-coupling via the RAS/ERK/CREB pathway. Membrane depolarization of HEK293 cells co-expressing α1.2 and α with Cavβ or Cavβ triggers constitutive transcriptional activation, which is correlated with facilitated channel activity. Similar to the Timothy-associated autistic mutation α1.2, 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 autistic mutants is consistent with Cavβ/Ras activation in ET coupling and implicates Rho signaling as yet another molecular pathway activated by Cavα1.2/Cavβ2 . Facilitated spontaneous channel activity preceding enhanced gene activation via the Ras/ERK/CREB pathway, appears a general molecular mechanism for Ca channel mediated ASD and other neurodevelopmental disorders.