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 alpha 11.2, or beta 2d, are associated with neurodevelopmental disorders such as ASD. Here, we found that two mutations S143F and G113S within the rat Cav beta 2a corresponding to autistic related mutations Cav beta 2d S197F and Cav beta 2d G167S in the human Cav beta 2d, activate ET -coupling via the RAS/ERK/CREB pathway. Membrane depolarization of HEK293 cells co-expressing alpha 11.2 and alpha 26 with Cav beta 2a S143F or Cav beta 2aG113Striggers constitutive transcriptional activation, which is correlated with facili-tated channel activity. Similar to the Timothy-associated autistic mutation alpha 11.2G406R, constitutive gene acti-vation is attributed to a hyperpolarizing shift in the activation kinetics of Cav1.2. Pulldown of RasGRF2 and RhoGEF by wt and the Cav beta 2a autistic mutants is consistent with Cav beta 2/Ras activation in ET coupling and im-plicates Rho signaling as yet another molecular pathway activated by Cav alpha 11.2/Cav beta 2 . Facilitated spontaneous channel activity preceding enhanced gene activation via the Ras/ERK/CREB pathway, appears a general mo-lecular mechanism for Ca2+ channel mediated ASD and other neurodevelopmental disorders.