Systematic identification of splice variants in human P/Q-type channel α,2.1 subunits: Implications for current density and Ca2+-dependent inactivation

Abstract

P/Q-type (Cav2.1) calcium channels support a host of Ca2+ driven neuronal functions in the mammalian brain. Alternative splicing of the main α1A (α12.1) subunit of these channels may thereby represent a rich strategy for tuning the functional profile of diverse neurobiological processes. Here, we applied a recently developed "transcript-scanning" method for systematic determination of splice variant transcripts of the human α12.1 gene. This screen identified seven loci of variation, which together have never been fully defined in humans. Genomic sequence analysis clarified the splicing mechanisms underlying the observed variation. Electrophysiological characterization and a novel analytical paradigm, termed strength-current analysis, revealed that one focus of variation, involving combinatorial inclusion and exclusion of exons 43 and 44, exerted a primary effect on current amplitude and a corollary effect on Ca2+-dependent channel inactivation. These findings significantly expand the anticipated scope of functional diversity produced by splice variation of P/Q-type channels.