Mutant cardiac ryanodine receptors and ventricular arrhythmias: is ?gain-of-function? obligatory?

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Abstract
See article by Thomas et al. [1] (pages 52–60) in this issue . In this issue of Cardiovascular Research, Thomas et al. [1] evidence functional differences among sudden cardiac death (SCD)-linked ryanodine receptors (RyR2) mutants. They challenge the conventional view that arrhythmogenic disorders associated with RyR2 mutations result exclusively from ‘gain-of-function’ channelopathies generating aberrant spontaneous Ca2+ release [2–4]. Thomas et al. [1] now report a ‘loss-of-function’ phenotype of one RyR2 mutant associated with SCD. The RyR2 is primarily involved in cardiac contractile function. At each heartbeat, membrane depolarization during an action potential (AP) activates voltage-dependent L-type Ca2+ channels (L-VDCC), generating transmembrane Ca2+ influx (ICaL). ICaL triggers Ca2+ release via sarcoplasmic reticulum (SR) Ca2+ release channels (RyR2). This Ca2+-induced Ca2+ release (CICR) amplification step provides the amount of Ca2+ required for contraction. Hence, RyR2 are a key element in the control of cardiac output. However, RyR2-released Ca2+ can, in turn, modify membrane potential by modulating Ca2+-sensitive sarcolemmal ion channels or transporters. Potential targets include, among others, L-VDCC, Ca2+-activated Cl− channels, IK1 channels, and the Na+/Ca2+ exchanger. The RyR2 contributes to the setting of normal sinusal automaticity [5], but disordered RyR2 activity generates ventricular arrhythmia [2–4,6]. Normal heart beating rate is fixed by the sinus node. Slow diastolic depolarization brings cellular membrane potential to a threshold, allowing the firing of an AP. RyR2 activity contributes to accelerate diastolic depolarization [7,8]. Indeed, the Ca2+ released during diastole by the RyR2 activates the Na+/Ca2+ exchanger in the forward mode. The resulting … *Corresponding author. Tel.: +33 467 41 52 41; fax: +33 467 41 52 42. E-mail address: srichard{at}montp.inserm.fr

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