RyR2 mutation-linked arrhythmogenic diseases and its therapeutic strategies

Abstract

The type 2 ryanodine receptor (RyR2) is a sarcoplasmic reticulum Ca²⁺ release channel that plays a central role in cardiac excitation-contraction coupling. Abnormal activity of the RyR2 is linked to abnormal Ca²⁺ signaling in cardiac cells, which often results in cardiac arrhythmias. For example, amino acid mutations in RyR2 have been reported to cause various types of arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation, and left ventricular non-compaction. At present, the total number of disease-associated RyR2 mutations exceeds 300. In addition, in chronic heart failure, modification of RyR2 by phosphorylation, oxidation or S-nitrosylation may cause abnormal channel activity. Arrhythmogenic mechanisms of these various disorders are not yet fully understood. We have recently established a method to quantitatively evaluate the effects of various arrhythmogenic mutations and modifications on RyR2 channels by using HEK293 expression system. We found that arrhythmogenic mutations in RyR2 are classified into two groups: gain-of-function and loss-of-function of the channel. Since they are indistinguishable in clinical diagnosis, our analysis is very useful for diagnosis and choice of treatment strategies for RyR2-linked arrhythmogenic diseases. This review describes the current advances and issues of research on RyR2 mutation-related arrhythmogenic disorders.