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J. Biol. Chem., Vol. 283, Issue 23, 15997-16003, June 6, 2008

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Novel Splice Variants of Rat Ca_V2.1 That Lack Much of the Synaptic Protein Interaction Site Are Expressed in Neuroendocrine Cells^*

W. R. A. Kosala J. S. Rajapaksha¹², Daoyi Wang¹, Jonathan N. Davies³, Lina Chen, Gerald W. Zamponi⁴, and Thomas E. Fisher⁵

From the Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5 and the Hotchkiss Brain Institute, University of Calgary, Calgary Alberta T2N 4N1, Canada

Voltage-gated Ca²⁺ channels are responsible for the activation of the Ca²⁺ influx that triggers exocytotic secretion. The synaptic protein interaction (synprint) site found in the II–III loop of Ca_V2.1 and Ca_V2.2 mediates a physical association with synaptic proteins that may be crucial for fast neurotransmission and axonal targeting. We report here the use of nested PCR to identify two novel splice variants of rat Ca_V2.1 that lack much of the synprint site. Furthermore, we compare immunofluorescence data derived from antibodies directed against sequences in the Ca_V2.1 synprint site and carboxyl terminus to show that channel variants lacking a portion of the synprint site are expressed in two types of neuroendocrine cells. Immunofluorescence data also suggest that such variants are properly targeted to neuroendocrine terminals. When expressed in a mammalian cell line, both splice variants yielded Ca²⁺ currents, but the variant containing the larger of the two deletions displayed a reduced current density and a marked shift in the voltage dependence of inactivation. These results have important implications for Ca_V2.1 function and for the mechanisms of Ca_V2.1 targeting in neurons and neuroendocrine cells.

Received for publication, December 27, 2007 , and in revised form, February 20, 2008.

^* This work was supported by a grant from the Natural Sciences and Engineering Research Council of Canada (to T. E. F.). 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.

¹ Both authors contributed equally to this paper.

² Present address: Canadian Animal Genetic Resources Program, Agriculture and Agri-Food Canada, 107 Science Place, Saskatoon, Saskatchewan, Canada S7N 0X2.

³ Holds a Studentship from the Alberta Heritage Foundation for Medical Research (AHFMR).

⁴ An AHFMR Scientist and Canada Research Chair. Supported by a grant from the Canadian Institutes of Health Research.

⁵ To whom correspondence should be addressed: Dept. of Physiology, College of Medicine, University of Saskatchewan, 107 Wiggins Rd., Saskatoon, SK S7N 5E5, Canada. Tel.: 306-966-6528; Fax: 306-966-6532; E-mail: thomas.fisher{at}usask.ca.

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