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The Journal of Neuroscience, December 1, 2002, 22(23):10142-10152

Systematic Identification of Splice Variants in Human P/Q-Type Channel ₁2.1 Subunits: Implications for Current Density and Ca²⁺-Dependent Inactivation

Tuck Wah Soong^{1, 2, 3}, Carla D. DeMaria³, Rebecca S. Alvania^{3, 4}, Larry S. Zweifel⁴, Mui Cheng Liang¹, Scott Mittman^{5, 6}, William S. Agnew⁵, and David T. Yue^{3, 4}

¹ National Neuroscience Institute, Singapore 308433, ² Department of Physiology, National University of Singapore, Singapore 119260, and Departments of ³ Biomedical Engineering, ⁴ Neuroscience, ⁵ Physiology, and ⁶ Anesthesiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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 _1A (₁2.1) 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 ₁2.1 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.

Key words: alternative splicing; P/Q-type calcium channel; _1A subunit; ₁2.1 subunit; transcript scanning; human brain; Ca²⁺-dependent inactivation; calmodulin

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Copyright © 2002 Society for Neuroscience  0270-6474/02/222310142-11$05.00/0

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