Alternative splicing of the voltage-gated Ca2+ channel β4 subunit creates a uniquely folded N-terminal protein binding domain with cell-specific expression in the cerebellar cortex

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

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Ca2+ β channel subunits regulate cell-surface expression and gating of voltage-dependent Ca2+ channel α1 subunits. Based on primary sequence comparisons, β 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 β 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 β subunits (β14) 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 β4a 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 Cav2.1 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 β4 subunits, the interactions are specific for the β4a splice variant, because they do not occur with the β4b A domain. These results have strong bearing on our current understanding of the structure of alternatively spliced Ca2+ channel β subunits and the cell-specific roles they play in the CNS.

Original languageEnglish (US)
Pages (from-to)2635-2644
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number10
DOIs
StatePublished - Mar 8 2006
Externally publishedYes

Keywords

  • Alternative splicing
  • Ca channel
  • Molecular layer of cerebellum
  • Protein structure
  • Synaptotagmin
  • β subunit

ASJC Scopus subject areas

  • General Neuroscience

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