Store-dependent deactivation: Cooling the chain-reaction of myocardial calcium signaling

Abstract

In heart cells, Ca2+ released from the internal storage unit, the sarcoplasmic reticulum (SR) through ryanodine receptor (RyR2) channels is the predominant determinant of cardiac contractility. Evidence obtained in recent years suggests that SR Ca2+ release is tightly regulated not only by cytosolic Ca2+ but also by intra-store Ca2+ concentration. Specifically, Ca2+-induced Ca2+ release (CICR) that relies on auto-catalytic action of Ca2+ at the cytosolic side of RyR2s is precisely balanced and counteracted by RyR2 deactivation dependent on a reciprocal decrease of Ca2+ at the luminal side of RyR2s. Dysregulation of this inherently unstable Ca2+ signaling is considered to be an underlying cause of triggered arrhythmias, and is associated with genetic and acquired forms of sudden cardiac death. In this article, we present an overview of recent advances in our understanding of the regulatory role luminal Ca2+ plays in Ca2+ handling, with a particular emphasis on the role of Ca2+ release refractoriness in aberrant Ca2+ release. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.

Decreased RyR2 refractoriness determines myocardial synchronization of aberrant Ca 2+ release in a genetic model of arrhythmia

“…Our results are consistent with and expand on previous findings obtained from a postmyocardial infarction canine model of arrhythmia (31) that showed impaired Ca 2+ store-dependent deactivation and compromised Ca 2+ release refractoriness in isolated myocytes (33). Our findings are supported by experiments in whole hearts of CASQ2 −/− mice that evidenced shortened Ca 2+ release restitution (37).…”

“…Based on our findings and results of previous studies (33)(34)(35)(36), the mechanism of DCR synchronization in CASQ2 R33Q myocardium depends on the efficiency of store-dependent RyR2 deactivation. In normal myocytes, reduction of luminal Ca 2+ following release prompts RyR2s to deactivate via CASQ2, thereby rendering SR release refractory to spontaneous reactivation (7).…”

There and back again: Iterating between population-based modeling and experiments reveals surprising regulation of calcium transients in rat cardiac myocytes

“…For example, Ca 2+ -induced Ca 2+ release assumes release from a homogeneous population of ryanodine receptors, rather than more realistic stochastic triggering of local release events (Ca 2+ sparks) [59], a property that is essential for proper modeling of graded CICR [4]. Additionally, the phenomenological calcium release mechanism does not simulate realistic local depletion of SR [Ca 2+ ], an effect that is known to be important for proper termination of Ca 2+ release [60, 61]. However, as the experimental results demonstrate, phenomenological models that lack mechanistic details of Ca 2+ release can still be useful for addressing questions that depend primarily on the balance of fluxes across the cellular and SR membranes [21].…”

Hyperphosphorylation of RyRs Underlies Triggered Activity in Transgenic Rabbit Model of LQT2 Syndrome

“…This is in contrast to spontaneously generated Ca 2+ waves that have been found to promote EADs under the combined influence of Ca 2+ overload and β-adrenergic stimulation (36). Ca 2+ waves have also been traditionally invoked as a mechanism of delayed afterdepolarizations (DADs) (37,38). Hence, in this broader context of Ca 2+ -triggered arrhythmias, a major novel finding of the present study is that abnormal Ca 2+ handling can promote EAD formation under a condition where the SR load is dramatically reduced and aberrant Ca 2+ releases are predominantly triggered by Ca 2+ influx through LTCCs.…”