RyRCa2+ leak limits cardiac Ca2+ window current overcoming the tonic effect of calmodulinin mice
María Fernández-Velasco1, Gema Ruiz-Hurtado, Angélica Rueda
1Inserm, U637, Université Montpellier-1, Université Montpellier-2, Montpellier, France.
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.
Insights
Calcium sparks from the sarcoplasmic reticulum (SR) impact L-type Ca(2+) channels (LTCC) in catecholaminergic polymorphic ventricular tachycardia (CPVT) mice. This SR Ca(2+) leak alters LTCC gating, reducing cardiac window current.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Calcium Signaling
Background:
- Calcium (Ca2+) ions mediate functional coupling between L-type Ca2+ channels (LTCC) and sarcoplasmic reticulum (SR) Ca2+ release channels (ryanodine receptors, RyR).
- This interaction is crucial for cardiac excitation-contraction coupling and involves Ca2+-induced Ca2+ release (CICR) and Ca2+-dependent inactivation (CDI) of LTCC.
- CDI is thought to be regulated by local Ca2+ signaling within nanodomains, involving calmodulin (CaM).
Purpose of the Study:
- To investigate the impact of RyR-mediated Ca2+ leak on LTCC gating in a mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT).
- To elucidate the role of local Ca2+ signaling and CaM in modulating LTCC function during pathological Ca2+ release events.
Main Methods:
- Electrophysiological analysis of LTCC currents in CPVT mice and wild-type (WT) cells.
- Manipulation of intracellular Ca2+ buffering and SR Ca2+ load.
- Induction of RyR Ca2+ leak using Ryanodol and CaM inhibition in WT cells.
Main Results:
- Increased Ca2+ sparks in CPVT mice caused a depolarizing shift in LTCC activation and a hyperpolarizing shift in inactivation, reducing the LTCC window current.
- Enhanced Ca2+ buffering or SR Ca2+ depletion attenuated these LTCC gating modifications.
- RyR Ca2+ leak induced by Ryanodol and CaM inhibition mimicked these effects in WT cells, highlighting CaM's role.
Conclusions:
- RyR-generated Ca2+ leak significantly alters LTCC gating through localized Ca2+ signaling and CaM-dependent mechanisms.
- This study reveals a novel paradigm for CaM's influence on LTCC gating and underscores the importance of spatio-temporal Ca2+ dynamics in cardiac function.
- Understanding these interactions is critical for addressing pathophysiological conditions involving Ca2+ dysregulation.
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