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

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.

STIM1–Ca 2+ signaling modulates automaticity of the mouse sinoatrial node

“…Our studies also reveal enhanced vagal tone in cSTIM1 −/− mice, which would reduce the basal activity of L-type Ca 2+ channels. Taken together, our findings support the idea that depletion of SR Ca 2+ stores of cSTIM1 −/− SANCs induced a Ca 2+ -dependent decrease in L-type Ca 2+ currents, much as in CPVT mice (31,32).…”

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

“…Thus, taken together, the higher Ca 2+ released as Ca 2+ sparks ( Figure 7F) and LDCR indicates enhancement of the Ca 2+ clock, but the CL remained unexpectedly longer. As shown in Figure 4 (52). Here, our data indicate depressed I CaL ( Figure 4C and Figure 5D) and a smaller amount of Ca 2+ stored in the SR ( Figure 6A) in KI SAN cells compared with WT.…”

“…These data point to an intrinsic defect of the RyR 2 R420Q function rather than expression or basal phosphorylation difference. Figure 7A, right), as in some other CPVT1 models (15,16,25). To further examine RyR 2 R420Q function, we analyzed Ca 2+ spark characteristics.…”

Sustained Epac activation induces calmodulin dependent positive inotropic effect in adult cardiomyocytes

“…This effect could be dependent on CaM. In fact, CaM-dependent shifts in the activation curve have been recently reported [21,24].…”

“…S4). Thus, Epac chronic activation could increase Ca 2+ entry through L-type Ca 2+ channels participating to SR Ca 2+ load increase [21].…”