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J. Biol. Chem., Vol. 282, Issue 40, 29211-29221, October 5, 2007

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A Novel Ca_V1.2 N Terminus Expressed in Smooth Muscle Cells of Resistance Size Arteries Modifies Channel Regulation by Auxiliary Subunits^*

Xiaoyang Cheng¹, Jianxi Liu, Maria Asuncion-Chin, Eva Blaskova, John P. Bannister, Alejandro M. Dopico, and Jonathan H. Jaggar²

From the Departments of Physiology and Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Voltage-dependent L-type Ca²⁺ (Ca_V1.2) channels are the principal Ca²⁺ entry pathway in arterial myocytes. Ca_V1.2 channels regulate multiple vascular functions and are implicated in the pathogenesis of human disease, including hypertension. However, the molecular identity of Ca_V1.2 channels expressed in myocytes of myogenic arteries that regulate vascular pressure and blood flow is unknown. Here, we cloned Ca_V1.2 subunits from resistance size cerebral arteries and demonstrate that myocytes contain a novel, cysteine rich N terminus that is derived from exon 1 (termed "exon 1c"), which is located within CACNA1C, the Ca_V1.2 gene. Quantitative PCR revealed that exon 1c was predominant in arterial myocytes, but rare in cardiac myocytes, where exon 1a prevailed. When co-expressed with ₂ subunits, Ca_V1.2 channels containing the novel exon 1c-derived N terminus exhibited: 1) smaller whole cell current density, 2) more negative voltages of half activation (V_1/2,act) and half-inactivation (V_1/2,inact), and 3) reduced plasma membrane insertion, when compared with channels containing exon 1b. _1b and _2a subunits caused negative shifts in the V_1/2,act and V_1/2,inact of exon 1b-containing Ca_V1.2₁/₂ currents that were larger than those in exon 1c-containing Ca_V1.2₁/₂ currents. In contrast, ₃ similarly shifted V_1/2,act and V_1/2,inact of currents generated by exon 1b- and exon 1c-containing channels. subunits isoform-dependent differences in current inactivation rates were also detected between N-terminal variants. Data indicate that through novel alternative splicing at exon 1, the Ca_V1.2 N terminus modifies regulation by auxiliary subunits. The novel exon 1c should generate distinct voltage-dependent Ca²⁺ entry in arterial myocytes, resulting in tissue-specific Ca²⁺ signaling.

Received for publication, November 15, 2006 , and in revised form, June 20, 2007.

^* This study was supported by grants from the National Institutes of Health (to J. H. J., HL67061 and HL77678; and A. M. D., AA11560 and HL77424) and the American Heart Association National Center (to J. H. J.). 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 supplemental Table S1.

The nucleotide sequence(s) reported in this paper has been submitted to the Gen-Bank^TM/EBI Data Bank with accession number(s) DQ538522 [GenBank] and AY974797 [GenBank] .

¹ Recipient of a predoctoral fellowship from the Southeast Affiliate of the American Heart Association.

² To whom correspondence should be addressed: Dept. of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163. Tel.: 901-448-1208; Fax: 901-448-7126; E-mail: jjaggar{at}physio1.utmem.edu.

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