Molecular and functional study of splice variations of the L-type voltage-gated calcium channel CaV1.2 alpha1-subunit

Abstract

L-type (CaV1.2) voltage-gated calcium channels play critical roles in membrane excitability, gene expression, cardiac and smooth muscle contraction. Alternative splicing enriches the functional diversity of the pore-forming CaV1.2 alpha-1 subunit. Systematic screening of the human CaV1.2 alpha-1 gene by the transcript-scanning method revealed 19 of the 55 exons were subjected to alternative splicing, and two of these were novel exons. A large IVS3-S4 variability resulting from combinatorial utilization of exons 31-33 demonstrated a correlation between increased IVS3-S4 linker length and more depolarized activation potentials.Sixty-four splicing profiles of CaV1.2 alpha-1 subunit were identified from 6 full-length cDNA libraries generated from heart and aortic tissues of the Spontaneously Hypertensive Rats and Wistar Kyoto Rats. The tissue-selective and pathologically induced splicing profiles of 10 alternatively spliced exons assessed indicated a striking alteration in exon utilization and splicing patterns. This study provides essential evidence for the molecular diversity of CaV1.2 calcium channels in the cardiovascular system.