Effects of RyR2 specific inhibitors on arrhythmia in CPVT model mice

Ryanodine receptor 2 (RyR2) is the major Ca2+ release channel on the sarcoplasmic reticulum (SR) and plays a central role in EC-coupling in the heart. Abnormal activation of RyR2 by gain-of-function mutations such as catecholaminergic polymorphic ventricular tachycardia (CPVT)-linked mutations is known to increase propensity of spontaneous Ca2+ release from SR and causes ventricular arrythmia. In such cases, drugs that suppress RyR2 activity are expected to have anti-arrhythmic effects. However, this hypothesis has not been directly tested since no specific RyR2 inhibitors had been identified yet. We recently searched for RyR2 inhibitors utilizing a high-throughput screening procedure with HEK293 cells expressing RyR2 and an ER Ca2+ indicator (Murayama et al., Mol Pharmacol, 2018), and found several compounds that inhibited RyR2 but not RyR1. Furthermore, we successfully synthesized structural analogs from one of hit compounds with much higher affinity. In this study, we examined the effects of these newly found RyR2 inhibitors on arrhythmia in CPVT model mice which have a gain-of-function mutation in RyR2 and exhibit abnormal Ca2+ and membrane potential signals in their cardiomyocytes. Our results suggest that RyR2 inhibitors are promising antiarrhythmic drug candidates for arrhythmia in CPVT patients.