2024-03-28T14:19:59Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/399182021-12-28T16:39:14Zcom_10261_22com_10261_1com_10261_86col_10261_275col_10261_339
RyRCa2+ leak limits cardiac Ca2+ window current overcoming the tonic effect of calmodulinin mice
Fernández-Velasco, María
Ruiz-Hurtado, Gema
Delgado, Carmen
Benitah, Jean-Pierre
Pig ventricular myocytes
Channel inactivation
Calcium-channels
Ryanodine receptors
Sarcoplasmic-reticulum
Dependent inactivation
Intracellular ca2+
Alpha(1c) subunit
This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.
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.
2011-09-23T11:16:49Z
2011-09-23T11:16:49Z
2011-06-06
artículo
PLoS ONE 6(6): e20863 (2010)
http://hdl.handle.net/10261/39918
10.1371/journal.pone.0020863
1932-6203
21673970
eng
Publisher’s version
http://dx.doi.org/10.1371/journal.pone.0020863
openAccess
Public Library of Science