Elevated basal transcription can underlie timothy channel association with autism related disorders

Timothy syndrome (TS) is a neurodevelopmental disorder caused by mutations in the pore-forming subunit α₁1.2 of the L-type voltage-gated Ca²⁺-channel Cav1.2, at positions G406R or G402S. Although both mutations cause cardiac arrhythmias, only Cav1.2^G406R is associated with the autism-spectrum-disorder (ASD). We show that transcriptional activation by Cav1.2^G406R and Cav1.2^G402S is driven by membrane depolarization through the Ras/ERK/CREB pathway in a process called excitation-transcription (ET) coupling, as previously shown for wt Cav1.2. This process requires the presence of the intracellular β-subunit of the channel. We found that only the autism-associated mutant Cav1.2^G406R, as opposed to the non-autistic mutated channel Cav1.2^G402S, exhibits a depolarization-independent CREB phosphorylation, and spontaneous transcription of cFos and MeCP2. A leftward voltage-shift typical of Cav1.2^G406R activation, increases channel opening at subthreshold potentials, resulting in an enhanced channel activity, as opposed to a rightward shift in Cav1.2^G402S. We suggest that the enhanced spontaneous Cav1.2^G406R activity accounts for the increase in basal transcriptional activation. This uncontroled transcriptional activation may result in the manifestation of long-term dysregulations such as autism. Thus, gating changes provide a mechanistic framework for understanding the molecular events underlying the autistic phenomena caused by the G406R Timothy mutation. They might clarify whether a constitutive transcriptional activation accompanies other VGCC that exhibit a leftward voltage-shift of activation and are also associated with long-term cognitive disorders.