Systematic Identification of Splice Variants in Human P/Q-Type Channel α₁2.1 Subunits: Implications for Current Density and Ca²⁺-Dependent Inactivation

Abstract

P/Q-type (Ca_v2.1) calcium channels support a host of Ca²⁺-driven neuronal functions in the mammalian brain. Alternative splicing of the main α_1A(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.