Mechanism of Cav1.2 channel modulation by the amino terminus of cardiac β2-subunits

Stefan Herzig, Ismail F.Y. Khan, Dirk Gründemann, Jan Matthes, Andreas Ludwig, Guido Michels, Uta C. Hoppe, Dipayan Chaudhuri, Arnold Schwartz, David T. Yue, Roger Hullin

Research output: Contribution to journalArticle

Abstract

L-type calcium channels are composed of a pore, α1c (CaV1.2), and accessory β- and α2δ- subunits. The β-subunit core structure was recently resolved at high resolution, providing important information on many functional aspects of channel modulation. In this study we reveal differential novel effects of five β2-subunits isoforms expressed in human heart (β2a-e) on the single L-type calcium channel current. These splice variants differ only by amino-terminal length and amino acid composition. Single-channel modulation by β2-subunit isoforms was investigated in HEK293 cells expressing the recombinant L-type ion conducting pore. All β2-subunits increased open probability, availability, and peak current with a highly consistent rank order (β 2a≈β2b2e≈β 2c2d). We show graded modulation of some transition rates within and between deep-closed and inactivated states. The extent of modulation correlates strongly with the length of amino-terminal domains. Two mutant β2-subunits that imitate the natural span related to length confirm this conclusion. The data show that the length of amino termini is a relevant physiological mechanism for channel closure and inactivation, and that natural alternative splicing exploits this principle for modulation of the gating properties of calcium channels.

Original languageEnglish (US)
Pages (from-to)1527-1538
Number of pages12
JournalFASEB Journal
Volume21
Issue number7
DOIs
StatePublished - May 1 2007

Keywords

  • Calcium channel subunit
  • Cardiac electrophysiology
  • Dihydropyridine

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Herzig, S., Khan, I. F. Y., Gründemann, D., Matthes, J., Ludwig, A., Michels, G., Hoppe, U. C., Chaudhuri, D., Schwartz, A., Yue, D. T., & Hullin, R. (2007). Mechanism of Cav1.2 channel modulation by the amino terminus of cardiac β2-subunits. FASEB Journal, 21(7), 1527-1538. https://doi.org/10.1096/fj.06-7377com