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Alternative splicing of Ca_v1.2 channel exons in smooth muscle cells of resistance-size arteries generates currents with unique electrophysiological properties

Departments of ¹Physiology and ²Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 30 January 2009 ; accepted in final form 1 June 2009

Voltage-dependent calcium (Ca²⁺, Ca_V1.2) channels are the primary Ca²⁺ entry pathway in smooth muscle cells of resistance-size (myogenic) arteries, but their molecular identity remains unclear. Here we identified and quantified Ca_V1.2 ₁-subunit splice variation in myocytes of rat resistance-size (100–200 µm diameter) cerebral arteries. Full-length clones containing either exon 1b or the recently identified exon 1c exhibited additional primary splice variation at exons 9*, 21/22, 31/32, and ± 33. Real-time PCR confirmed the findings from full-length clones and indicated that the major Ca_V1.2 variant contained exons 1c, 8, 21, and 32+33, with 57% containing 9*. Exon 9* was more prevalent in clones containing 1c (72%) than in those containing 1b (33%), suggesting exon-selective combinatorial splicing. To examine the functional significance of this splicing profile, membrane currents produced by each of the four exon 1b/c/ ± 9* variants were characterized following transfection in HEK293 cells. Exon 1c and 9* caused similar hyperpolarizing shifts in both current-voltage relationships and voltage-dependent activation of currents. Furthermore, exon 9* induced a hyperpolarizing shift only in the voltage-dependent activation of channels containing exon 1b, but not in those containing exon 1c. In contrast, exon 1b, 1c, or +9* did not alter voltage-dependent inactivation. In summary, we have identified the Ca_V1.2 ₁-subunit splice variant population that is expressed in myocytes of resistance-size arteries and the unique electrophysiological properties of recombinant channels formed by exon 1 and 9* variation. The predominance of exon 1c and 9* in smooth muscle cell Ca_V1.2 channels causes a hyperpolarizing shift in the voltage sensitivity of currents toward the physiological arterial voltage range.

voltage-dependent calcium channel; myogenic artery; cloning; ribonucleic acid splicing

This article has been cited by other articles:

				M. A. Nystoriak, K. Murakami, P. L. Penar, and G. C. Wellman Cav1.2 splice variant with exon 9* is critical for regulation of cerebral artery diameter Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1820 - H1828. [Abstract] [Full Text] [PDF]