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J. Biol. Chem., Vol. 279, Issue 43, 44335-44343, October 22, 2004

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Transcript Scanning Reveals Novel and Extensive Splice Variations in Human L-type Voltage-gated Calcium Channel, Ca_v1.2 ₁ Subunit^*

Zhen Zhi Tang, Mui Cheng Liang, Songqing Lu, Dejie Yu, Chye Yun Yu, David T. Yue¶||, and Tuck Wah Soong¶**

From the Department of Physiology, National University of Singapore, Singapore 117597, National Neuroscience Institute, Singapore 308433, Singapore, and the Departments of ^¶Biomedical Engineering and ^||Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

The L-type (Ca_v1.2) voltage-gated calcium channels play critical roles in membrane excitability, gene expression, and muscle contraction. The generation of splice variants by the alternative splicing of the poreforming Ca_v1.2 ₁-subunit (₁1.2) may thereby provide potent means to enrich functional diversity. To date, however, no comprehensive scan of ₁ 1.2 splice variation has been performed, particularly in the human context. Here we have undertaken such a screen, exploiting recently developed "transcript scanning" methods to probe the human gene. The degree of variation turns out to be surprisingly large; 19 of the 55 exons comprising the human ₁1.2 gene were subjected to alternative splicing. Two of these are previously unrecognized exons and two others were not known to be spliced. Comparisons of fetal and adult heart and brain uncovered a large IVS3-S4 variability resulting from combinatorial utilization of exons 31–33. Electrophysiological characterization of such IVS3-S4 variation revealed unmistakable shifts in the voltage dependence of activation, according to an interesting correlation between increased IVS3-S4 linker length and activation at more depolarized potentials. Steady-state inactivation profiles remained unaltered. This systematic portrait of splice variation furnishes a reference library for comprehending combinatorial arrangements of Ca_v1.2 splice exons, especially as they impact development, physiology, and disease.

Received for publication, June 23, 2004 , and in revised form, August 5, 2004.

^* This work was supported by the National Medical Research Council and the Biomedical Research Council (to T. W. S.) and SCOR Grant P01HL52307-10 from the National Institutes of Health (to D. T. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Tables S1 and S2 and Figs. A and B.

^** To whom correspondence should be addressed: Dept. of Physiology, Faculty of Medicine, National University of Singapore, Blk MD9, 2 Medical Dr., Singapore 117597, Singapore. Tel.: 65-63577611; Fax: 65-62569178; E-mail: phsstw{at}nus.edu.sg.

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