Distinctive Inactivation Profiles of CaV1.2 Channels Encoding Different Timothy Syndrome Mutations in Various Alternative Splicing Backgrounds

Abstract

Timothy Syndrome is a CaV1.2 channelopathy, wherein mutations in the S6 segment of domain II affect channel inactivation. Interestingly, different mutations (G402S or G406R) within alternatively spliced exons (8a or 8) entail characteristic disease phenotypes, including autism, syndactyly, and long QT syndrome. Investigating Timothy Syndrome thereby promises mechanistic traction into these complex outcomes. The prevalence and distribution of channels bearing exon 8 versus 8a may explain some phenotypic variation. Here, we examine such variation at a more fundamental level, resolving intrinsic differences of inactivation among distinct mutant channels. Specifically, CaV1.2 inactivation comprises two separate mechanisms, voltage-dependent inactivation (VDI), and Ca2+/calmodulin-mediated inactivation (CDI) (Barrett & Tsien PNAS 2008). Systematic mutagenesis of S6 domains in CaV1.3 suggest that VDI and CDI alterations can be dissociated, and changes in channel activation are likely (Tadross et al, this meeting). Our data here furnish remarkable examples of differing CDI/VDI effects (a, wild-type, with Ba2+ current decay showing VDI, and Ca2+ decay showing CDI; b, c, distinct CDI/VDI alterations). It would be interesting if distinctive disease phenotypes and therapeutics ultimately correspond to specified deficits of VDI, CDI, or both.View Large Image | View Hi-Res Image | Download PowerPoint Slide