New short splice variants of the human cardiac Cavβ 2 subunit: Redefining the major functional motifs implemented in modulation of the Cav1.2 channel

Jo Beth Harry, Evgeny Kobrinsky, Darrell R. Abernethy, Nikolai M. Soldatov

Research output: Contribution to journalArticlepeer-review

Abstract

Two new short splice variants of the Ca2+ channel β2 subunit were cloned from human heart poly(A)(+) mRNA. The 410-amino acid β2f subunit is encoded by exons 1A, 2A, 3, 4, 12, 13, and 14 of the human Cavβ2 gene and lacks the protein kinase A phosphorylation site, the β-interaction domain (De Waard, M., Pragnell, M., and Campbell, K. P. (1994) Neuron 13, 495-503), 40% of the β-SH3 domain, and 73% of the guanylate kinase domain of the putative membrane-associated guanylate kinases module (McGee, A. W., Nunziato, D. A., Maltez, J. M., Prehoda, K. E., Pitt, G. S., and Bredt, D. S. (2004) Neuron 42, 89-99), and helix α3 of the α1-subunit binding pocket (Van Petegem F., Clark, K. A., Chatelain, F. C., and Minor, D. L., Jr. (2004) Nature 429, 071-075). The β2g transcript has two potential initiation codons. With the second ATG codon, it generates the 164-amino acid β2Δg subunit encoded essentially by the distal part of exon 14, and thus β2Δg completely lacks any of the above motifs. Immunoprecipitation analysis confirmed stable association of β2f and β2Δg with the α1C subunit. The plasma membrane localization of β2f and β2Δg was substantially increased by co-expression of the α1C,77 and α2δ subunits. In COS1 cells, β2f and β2Δg increased plasma membrane targeting of the pore-forming α1C subunit and differentially facilitated (β2f > β2Δg) the voltage gating of otherwise silent Cav1.2 channels. We conclude that it is unlikely that the β-interaction domain, membrane-associated guanylate kinases module, and the α1-subunit binding pocket helix α3 are essential for the interaction of the α1C and β2 subunits and suggest that in addition to the α1-subunit binding pocket helices α5 and α8, a yet unresolved C-terminal β2 region plays a crucial role.

Original languageEnglish (US)
Pages (from-to)46367-46372
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number45
DOIs
StatePublished - Nov 5 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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