Ryanodine receptor as a new therapeutic target of heart failure and lethal arrhythmia

Abstract

Abnormal intracellular Ca2+ handling by the sarcoplasmic reticulum (SR) is a critical factor in the development of heart failure (HF). Not only decreased Ca2+ uptake, but also uncoordinated Ca 2+ release plays a significant role in contractile and relaxation dysfunction. Spontaneous Ca2+ release through ryanodine receptor (RyR) 2, a huge tetrameric protein, during diastole leads to a decrease in the SR Ca2+ content, and also triggers delayed afterdepolarization that is a substrate for lethal arrhythmia. Several disease-linked mutations of RyR have been reported hi patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) or arrhythmogenic right ventricular cardiomyopathy type 2 (ARVC2). The unique distribution of these mutation sites has lead to the concept that an interaction among the putative regulatory domains within RyR may play a key role in regulating channel opening, and that there seems to be a common abnormality in the channel disorder of HF and CPVT/ARVC2. Recent knowledge gained from pathological conditions may lead to the development of a new therapeutic strategy for the treatment of HF or cardiac arrhythmia.