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

María Fernández-Velasco, Gema Ruiz-Hurtado, Angélica Rueda, Patricia Neco, Martha Mercado-Morales, Carmen Delgado, Carlo Napolitano, Silvia G. Priori, Sylvain Richard, Ana MaríaGómez, Jean Pierre Benitah

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numbere20863
JournalPLoS One
Volume6
Issue number6
DOIs
Publication statusPublished - 2011

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Sarcoplasmic Reticulum
Calmodulin
Ryanodine Receptor Calcium Release Channel
calcium
mice
Crosstalk
Electric sparks
Buffers
sarcoplasmic reticulum
Chemical activation
calmodulin
ryanodine receptors
inactivation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Fernández-Velasco, M., Ruiz-Hurtado, G., Rueda, A., Neco, P., Mercado-Morales, M., Delgado, C., ... Benitah, J. P. (2011). RyRCa2+ leak limits cardiac Ca2+ window current overcoming the tonic effect of calmodulinin mice. PLoS One, 6(6), [e20863]. https://doi.org/10.1371/journal.pone.0020863

RyRCa2+ leak limits cardiac Ca2+ window current overcoming the tonic effect of calmodulinin mice. / Fernández-Velasco, María; Ruiz-Hurtado, Gema; Rueda, Angélica; Neco, Patricia; Mercado-Morales, Martha; Delgado, Carmen; Napolitano, Carlo; Priori, Silvia G.; Richard, Sylvain; MaríaGómez, Ana; Benitah, Jean Pierre.

In: PLoS One, Vol. 6, No. 6, e20863, 2011.

Research output: Contribution to journalArticle

Fernández-Velasco, M, Ruiz-Hurtado, G, Rueda, A, Neco, P, Mercado-Morales, M, Delgado, C, Napolitano, C, Priori, SG, Richard, S, MaríaGómez, A & Benitah, JP 2011, 'RyRCa2+ leak limits cardiac Ca2+ window current overcoming the tonic effect of calmodulinin mice', PLoS One, vol. 6, no. 6, e20863. https://doi.org/10.1371/journal.pone.0020863
Fernández-Velasco M, Ruiz-Hurtado G, Rueda A, Neco P, Mercado-Morales M, Delgado C et al. RyRCa2+ leak limits cardiac Ca2+ window current overcoming the tonic effect of calmodulinin mice. PLoS One. 2011;6(6). e20863. https://doi.org/10.1371/journal.pone.0020863
Fernández-Velasco, María ; Ruiz-Hurtado, Gema ; Rueda, Angélica ; Neco, Patricia ; Mercado-Morales, Martha ; Delgado, Carmen ; Napolitano, Carlo ; Priori, Silvia G. ; Richard, Sylvain ; MaríaGómez, Ana ; Benitah, Jean Pierre. / RyRCa2+ leak limits cardiac Ca2+ window current overcoming the tonic effect of calmodulinin mice. In: PLoS One. 2011 ; Vol. 6, No. 6.
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