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The Journal of Neuroscience, March 8, 2006, 26(10):2635-2644; doi:10.1523/JNEUROSCI.0067-06.2006

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Cellular/Molecular
Alternative Splicing of the Voltage-Gated Ca²⁺ Channel ₄ Subunit Creates a Uniquely Folded N-Terminal Protein Binding Domain with Cell-Specific Expression in the Cerebellar Cortex

Andrew C. Vendel,¹ Mark D. Terry,¹ Amelia R. Striegel,¹ Nicole M. Iverson,¹ Valerie Leuranguer,¹ Christopher D. Rithner,² Barbara A. Lyons,³ Gary E. Pickard,¹ Stuart A. Tobet,¹ and William A. Horne¹

¹Department of Biomedical Sciences, College of Veterinary Medicine and Biomedical Sciences and ²Department of Chemistry, College of Natural Sciences, Colorado State University, Fort Collins, Colorado 80526, and ³Department of Chemistry and Biochemistry, College of Arts and Sciences, New Mexico State University, Las Cruces, New Mexico 88003

Correspondence should be addressed to Dr. William A. Horne, Department of Biomedical Sciences, 1617 Campus Delivery, Colorado State University, Fort Collins, CO 80523. Email: bill.horne{at}colostate.edu

Ca²⁺ channel subunits regulate cell-surface expression and gating of voltage-dependent Ca²⁺ channel 1 subunits. Based on primary sequence comparisons, subunits are predicted to be modular structures composed of five domains (A–E) that are related to the large family of membrane-associated guanylate kinase proteins. The crystal structure of the subunit core B–D domains has been reported recently; however, little is known about the structures of the A and E domains. The N-terminal A domain differs among the four subtypes of Ca²⁺ channel subunits (₁–₄) primarily as the result of two duplications of an ancestral gene containing multiple alternatively spliced exons. At least nine A domain sequences can be generated by alternative splicing. In this report, we focus on one A domain sequence, the highly conserved _4a A domain. We solved its three-dimensional structure and show that it is expressed in punctate structures throughout the molecular layer of the cerebellar cortex. We also demonstrate that it does not participate directly in Ca_v2.1 Ca²⁺channel gating but serves as a binding site in protein–protein interactions with synaptotagmin I and the LC2 domain of microtubule-associated protein 1A. With respect to ₄ subunits, the interactions are specific for the _4a splice variant, because they do not occur with the _4b A domain. These results have strong bearing on our current understanding of the structure of alternatively spliced Ca²⁺ channel subunits and the cell-specific roles they play in the CNS.

Key words: Ca²⁺ channel; _4a subunit; alternative splicing; protein structure; molecular layer of cerebellum; synaptotagmin

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Received Oct. 12, 2005; accepted Jan. 25, 2006.

Correspondence should be addressed to Dr. William A. Horne, Department of Biomedical Sciences, 1617 Campus Delivery, Colorado State University, Fort Collins, CO 80523. Email: bill.horne{at}colostate.edu

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