Abstract
Two domains within the ryanodine receptor（RyR2）of sarcoplasmic reticulum（SR）｛N-terminal（0-600）and central（2000-2500）domains：N-C domains｝，harboring many mutations in CPVT, was found to interact with each other as a regulatory switch for channel gating. Here, we investigated the role of inter-domain interaction in the pathogenesis of heart failure（HF）and lethal arrhythmia. In the SR from pacing-induced failing hearts, domain unzipping in N-C domains has already taken place. In failing（but not normal）cardiomyocytes, the frequency of Ca2+ sparks（SpF）was markedly increased at baseline. To assess whether the defective inter-domain interaction also causes CPVT, we developed knock-in（KI：RyR2R2474S/+）mice model harboring a human Arg-to-Ser（R2474S）mutation. In all KI mice, ventricular tachycardia was observed by exercise with treadmill. In response to isoproterenol（ISO），the SpF was markedly increased in KI, in association with the domain unzipping. Co-addition of dantrolene markedly diminished the SpF in both failing and KI cardiomyocytes. In conclusion, the defective inter-domain interaction within the RyR2 may induce the de-stabilized channel gating, as a common key mechanism of heart failure and lethal arrhythmia.
