Unzipping RyR2 in adult cardiomyocytes: Getting closer to mechanisms of inherited ventricular arrhythmias?

Abstract

See article by Yang et al. [19] (pages 475–485) in this issue . Malignant ventricular arrhythmias (VA) are a major cause of mortality and morbidity worldwide. Causative mechanisms are multiple and complex. VA can be generated by abnormal or instable repolarization of the action potential (AP) in myocytes. Perverted repolarization results mainly from congenital channelopathies, acquired diseases, including hypertrophy and heart failure (HF), or therapeutic intervention. Inherited arrhythmias are due to mutations, mostly in transmembrane ionic channels (Na+, K+, Ca2+) [1,2]. However, because Ca2+ regulates several ionic currents involved in AP repolarization [3], it was not counterintuitive to find that mutations in proteins regulating intracellular Ca2+ homeostasis can also generate VA and sudden cardiac death (SCD). For example, mutations in the cardiac Ca2+ release channel (ryanodine receptor; RyR2) of the sarcoplasmic reticulum (SR) are involved in type 2 arrhythmogenic right ventricular cardiomyopathy and catecholaminergic polymorphic ventricular tachycardia (CPVT) characterized by effort-induced VA in structurally normal hearts [2,4,5]. CPVT are also caused by mutations in calsequestrin, a protein binding Ca2+ and associated to the RyR2 in the lumenal side of the SR [2,4]. The intrinsic mechanisms by which changes in [Ca2+]i handling promote arrhythmias are not completely elucidated. Obviously, spontaneous SR Ca2+ release can activate a transient inward current ( I ti) mediated mainly by the electrogenic Na+/Ca2+ exchanger (NCX) in the forward mode [6] … * Corresponding author. Tel.: +33 467 41 52 41; fax: +33 467 41 52 42. Email address: srichard{at}montp.inserm.fr