[HTML][HTML] RyRCa2+ Leak Limits Cardiac Ca2+ Window Current Overcoming the Tonic Effect of Calmodulin in Mice

M Fernandez-Velasco, G Ruiz-Hurtado, A Rueda… - PLoS …, 2011 - journals.plos.org
M Fernandez-Velasco, G Ruiz-Hurtado, A Rueda, P Neco, M Mercado-Morales, C Delgado
PLoS One, 2011journals.plos.org
Ca2+ mediates the functional coupling between L-type Ca2+ channel (LTCC) and
sarcoplasmic reticulum (SR) Ca2+ release channel (ryanodine receptor, RyR), participating
in key pathophysiological processes. This crosstalk manifests as the orthograde Ca2+-
induced Ca2+-release (CICR) mechanism triggered by Ca2+ influx, but also as the
retrograde Ca2+-dependent inactivation (CDI) of LTCC, which depends on both Ca2+
permeating through the LTCC itself and on SR Ca2+ release through the RyR. This latter …
Ca2+ mediates the functional coupling between L-type Ca2+ channel (LTCC) and sarcoplasmic reticulum (SR) Ca2+ release channel (ryanodine receptor, RyR), participating in key pathophysiological processes. This crosstalk manifests as the orthograde Ca2+-induced Ca2+-release (CICR) mechanism triggered by Ca2+ influx, but also as the retrograde Ca2+-dependent inactivation (CDI) of LTCC, which depends on both Ca2+ permeating through the LTCC itself and on SR Ca2+ release through the RyR. This latter effect has been suggested to rely on local rather than global Ca2+ 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 Ca2+ leak, we evidence here that increased occurrence of the discrete local SR Ca2+ releases through the RyRs (Ca2+ 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 [Ca2+]i buffer capacity or depleting SR Ca2+ store blunted these changes, which could be reproduced in WT cells by RyRCa2+ leak induced with Ryanodol and CaM inhibition.Our results unveiled a new paradigm for CaM-dependent effect on LTCC gating and further the nanodomain Ca2+ control of LTCC, emphasizing the importance of spatio-temporal relationships between Ca2+ signals and CaM function.
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