Ca 2+ signaling amplification by oligomerization of L-type Ca v1.2 channels

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Ca 2+ influx via L-type Ca v1.2 channels is essential for multiple physiological processes, including gene expression, excitability, and contraction. Amplification of the Ca 2+ signals produced by the opening of these channels is a hallmark of many intracellular signaling cascades, including excitation-contraction coupling in heart. Using optogenetic approaches, we discovered that Ca v1.2 channels form clusters of varied sizes in ventricular myocytes. Physical interaction between these channels via their C-tails renders them capable of coordinating their gating, thereby amplifying Ca 2+ influx and excitation-contraction coupling. Light-induced fusion of WT Ca v1.2 channels with Ca v1.2 channels carrying a gain-of-function mutation that causes arrhythmias and autism in humans with Timothy syndrome (Ca v1.2-TS) increased Ca 2+ currents, diastolic and systolic Ca 2+ levels, contractility and the frequency of arrhythmogenic Ca 2+ fluctuations in ventricular myocytes. Our data indicate that these changes in Ca 2+ signaling resulted from Ca v1.2-TS increasing the activity of adjoining WT Ca v1.2 channels. Collectively, these data support the concept that oligomerization of Ca v1.2 channels via their C termini can result in the amplification of Ca 2+ influx into excitable cells.

Original languageEnglish (US)
Pages (from-to)1749-1754
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number5
DOIs
StatePublished - Jan 31 2012

Keywords

  • Calcium sparklets
  • Coupled gating
  • EC coupling
  • Voltage-gated calcium channels

ASJC Scopus subject areas

  • General

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