RyRCa2+ leak limits cardiac Ca2+ window current overcoming the tonic effect of calmodulinin mice

PLoS One. 2011;6(6):e20863. doi: 10.1371/journal.pone.0020863. Epub 2011 Jun 6.

Abstract

Ca(2+) mediates the functional coupling between L-type Ca(2+) channel (LTCC) and sarcoplasmic reticulum (SR) Ca(2+) release channel (ryanodine receptor, RyR), participating in key pathophysiological processes. This crosstalk manifests as the orthograde Ca(2+)-induced Ca(2+)-release (CICR) mechanism triggered by Ca(2+) influx, but also as the retrograde Ca(2+)-dependent inactivation (CDI) of LTCC, which depends on both Ca(2+) permeating through the LTCC itself and on SR Ca(2+) release through the RyR. This latter effect has been suggested to rely on local rather than global Ca(2+) signaling, which might parallel the nanodomain control of CDI carried out through calmodulin (CaM). Analyzing the CICR in catecholaminergic polymorphic ventricular tachycardia (CPVT) mice as a model of RyR-generated Ca(2+) leak, we evidence here that increased occurrence of the discrete local SR Ca(2+) releases through the RyRs (Ca(2+) sparks) cause a depolarizing shift in activation and a hyperpolarizing shift in isochronic inactivation of cardiac LTCC current resulting in the reduction of window current. Both increasing fast [Ca(2+)](i) buffer capacity or depleting SR Ca(2+) store blunted these changes, which could be reproduced in WT cells by RyRCa(2+) leak induced with Ryanodol and CaM inhibition.Our results unveiled a new paradigm for CaM-dependent effect on LTCC gating and further the nanodomain Ca(2+) control of LTCC, emphasizing the importance of spatio-temporal relationships between Ca(2+) signals and CaM function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Channels, L-Type / metabolism
  • Calcium Signaling* / drug effects
  • Calmodulin / antagonists & inhibitors
  • Calmodulin / metabolism*
  • Electric Conductivity*
  • Excitation Contraction Coupling / drug effects
  • Female
  • Gene Knock-In Techniques
  • Ion Channel Gating* / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sulfonamides / pharmacology
  • Tachycardia, Ventricular / metabolism
  • Tachycardia, Ventricular / pathology
  • Tachycardia, Ventricular / physiopathology

Substances

  • Calcium Channels, L-Type
  • Calmodulin
  • Ryanodine Receptor Calcium Release Channel
  • Sulfonamides
  • W 7
  • Calcium

Supplementary concepts

  • Polymorphic catecholergic ventricular tachycardia