title: RyRCa2+ leak limits cardiac Ca2+ window current overcoming the tonic effect of calmodulinin 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) 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.
authors.affiliation: Inserm, U637, Université Montpellier-1, Université Montpellier-2, Montpellier, France.
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Velasco
authors.forename: Gema
authors.initials: G
authors.lastname: Ruiz-Hurtado
authors.forename: Angélica
authors.initials: A
authors.lastname: Rueda
authors.forename: Patricia
authors.initials: P
authors.lastname: Neco
authors.forename: Martha
authors.initials: M
authors.lastname: Mercado-Morales
authors.forename: Carmen
authors.initials: C
authors.lastname: Delgado
authors.forename: Carlo
authors.initials: C
authors.lastname: Napolitano
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.forename: Ana María
authors.initials: AM
authors.lastname: Gómez
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Benitah
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004553:Electric Conductivity; D056966:Excitation Contraction Coupling / Q000187:drug effects; D005260:Female; D055879:Gene Knock-In Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D020746:Calcium Channels, L-Type; D002147:Calmodulin; D019837:Ryanodine Receptor Calcium Release Channel; D013449:Sulfonamides; C017967:W 7; D002118:Calcium