Ryanodine receptor-targeting therapy against heart failure and lethal arrhythmia

ダントロレンによるリアノジン受容体を分子標的とした新しい心不全・不整脈治療(ミニ・レビュー : 小西賞受賞者)

Ryanodine receptor-targeting therapy against heart failure and lethal arrhythmia

Creators Kobayashi Shigeki

悪性高熱症,カテコラミン誘発性多形性心室頻拍症(Catecholaminergic polymorphic ventricular tachycardia:CPVT)や心不全においては,リアノジン受容体(骨格筋型:RyR1心筋型:RyR2)内のドメイン連関障害が,リアノジン受容体からのCa^2+漏出の原因と考えられている.悪性高熱症の治療薬であるダントロレンは,RyR1に結合し,RyR1内のドメイン連関障害を是正することによってRyR1からのCa^{2+}漏出を抑制する.同様に,イヌ心不全モデルやCPVT型knock-inマウスにおいてもダントンは,RyR2に結合し,RyR2からのCa^{2+}漏出を抑制し,心不全の進展やCPVTを抑制する.このように,ダントロレンはRyR2を分子標的とした新しい心不全･不整脈治療薬となることが期待される.

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 Ca^{2+} 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（Leu^{590}-Cys^{609}).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 Ca^{2+} 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.

[ISSN]0513-1731

[NCID]AN00243156