Innovation of treatment for malignant hyperthermia and arrhythmia by inhibition of abnormal intracellular Ca2+ release through the ryanodine receptor

丹曲林是一种治疗恶性高热的特效药，它不仅能抑制骨骼肌兰尼碱受体（RyR 1）的Ca^2+渗漏，而且能通过纠正RyR 2的N端（1-619个氨基酸）和中心（2000-2500个氨基酸）结构域之间的相互作用来抑制RyR 2的Ca^2+渗漏。在此，我们检查了1）丹曲林对慢性快速起搏诱导的心力衰竭犬模型中的Ca 2+释放和心肌细胞功能的作用，2）丹曲林在人CPVT相关的RyR 2 ^<R2474 S/+>敲入（KI）小鼠模型中的抗心律失常作用。在心力衰竭模型中，丹曲林纠正了衰竭心脏中RyR 2内有缺陷的结构域间相互作用，抑制了自发性Ca^2+渗漏，进而改善了衰竭心脏中的心肌细胞功能。在人CPVT相关RyR 2 ^<R2474 S/+>基因敲入（KI）小鼠模型中，丹曲林预防CPVT，推测是通过纠正RyR 2抑制内儿茶酚胺诱导的缺陷性结构域间相互作用和抑制Ca^<2+>通过RyR 2渗漏。因此，丹曲林可能具有治疗心力衰竭和致命性心律失常的潜力，特别是针对RyR 2。

Dantrolene, a specific drug for the treatment of malignant hyperthermia, was found to inhibit Ca^<2+> leak through not only the skeletal ryanodine receptor (RyR1), but also the cardiac ryanodine receptor (RyR2) by correcting the defective inter-domain interaction between N-terminal(1-619 amino acid) amd central (2000-2500 amino acid) domains of RyRs. Here, we examined 1)the effect of dantrolene on the Ca2+ release and cardiomyocyte function in chronic rapid pacing-induced heart failure dog model 2) the anti-arrhythmic effect of dantrolene in human CPVT-associated RyR2^<R2474S /+> knock-in (KI) mouse model. In heart failure model, dantrolene corrects defective inter-domain interactions within RyR2 in failing hearts, inhibits spontaneous Ca^<2+> leak, in turn improves cardiomyocyte function in failing hearts. In human CPVT-associated RyR2^<R2474S /+> knock-in (KI) mouse model, dantrolene prevents CPVT, presumably by correction of catecholamine-induced defective inter-domain interaction within RyR2inhibiting and inhibition of Ca^<2+> leak through RyR2. Thus, dantrolene may have a potential to treat heart failure and lethal arrhythmia, specifically targeting RyR2.