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RyRCa 2+ Leak Limits Cardiac Ca 2+ Window Current Overcoming the Tonic Effect of Calmodulin in Mice

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) causea depolarizing shift in activation and a hyperpolarizing shift inisochronic 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.
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Submitted on : Thursday, February 13, 2020 - 12:10:00 PM
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Maria Fernández-Velasco, Gema Ruiz-Hurtado, Angélica Rueda, Patricia Neco, Marta Mercado-Morales, et al.. RyRCa 2+ Leak Limits Cardiac Ca 2+ Window Current Overcoming the Tonic Effect of Calmodulin in Mice. PLoS ONE, Public Library of Science, 2011, 6 (6), pp.e20863. ⟨10.1371/journal.pone.0020863⟩. ⟨inserm-02477335⟩

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