Abstract
The inter-domain interaction between N-terminal(1-600)and central domains(2000-2500)of the ryanodine receptor(RyR)plays a critical role in channel gating in both skeletal(RyR1)and cardiac(RyR2)muscle RyR-s. We previously reported that dantrolene, a therapeutic agent for malignant hyperthermia(MH),prevented abnormal Ca2+ leak by correction of the defective inter-domain interaction between N-terminal and central domains in MH-type RyR. The amino acid sequence of the putative dantrolene binding site of cardiac RyR2 is identical with the RyR1(Leu590-Cys609).Here, we investigated the molecular mechanism and the in-vivo therapeutic effect of dantrolene against heart failure as well as lethal arrhythmia, in tachycardia-induced heart failure canine model and catecholaminergic polymorphic ventricular tachycardia(CPVT)-associated RyR2R2474S/+ knock-in(KI)mice model. Dantrolene specifically bound to the corresponding domain 601-620 in RyR2 by using a quartz crystal microbalance technique(a highly sensitive mass-measuring technique).Dantrolene was also found to correct defective inter-domain interactions within RyR2 in the both models, inhibited diastolic Ca2+ leak, in turn improved cardiomyocyte function in failing hearts and prevented bidirectional VT induced by injection of epinephrine or exercise in CPVT. Thus, dantrolene may have a potential to treat heart failure and lethal arrhythmia, specifically targeting RyR2.
