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

通过兰尼碱受体抑制细胞内异常Ca2+释放治疗恶性高热和心律失常的创新

• 批准号: 20591805
• 负责人: KOBAYASHI Shigeki
• 金额: $ 3万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591805/
• 关键词: 悪性高熱症; 心室頻拍症; 心不全; ダントロレン; リアノジン受容体; 不整脈

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.

丹曲林是一种治疗恶性高热的特异性药物，通过纠正 RyR 的 N 端（1-619 个氨基酸）和中央（2000-2500 个氨基酸）结构域之间有缺陷的结构域间相互作用，发现不仅可以通过骨骼兰尼碱受体（RyR1）而且可以通过心脏兰尼碱受体（RyR2）抑制 Ca^2+ 渗漏。在这里，我们检查了 1) 丹曲林对慢性快速起搏诱发的心力衰竭狗模型中 Ca2+ 释放和心肌细胞功能的影响 2) 丹曲林在人 CPVT 相关 RyR2^<R2474S />+> 敲入 (KI) 小鼠模型中的抗心律失常作用。在心力衰竭模型中，丹曲林纠正衰竭心脏中RyR2内有缺陷的域间相互作用，抑制自发Ca ^ 2+ 渗漏，进而改善衰竭心脏中的心肌细胞功能。在人类 CPVT 相关的 RyR2^<R2474S /+> 敲入 (KI) 小鼠模型中，dantrolene 预防 CPVT，可能是通过纠正儿茶酚胺诱导的 RyR2 抑制内有缺陷的域间相互作用以及抑制通过 RyR2 的 Ca^2+ 渗漏来预防 CPVT。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 RyR2。

项目成果

Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure

• DOI: 10.1093/cvr/cvq108
• 发表时间: 2010-09-01
• 期刊: CARDIOVASCULAR RESEARCH
• 影响因子: 10.8
• 作者: Ono, Makoto;Yano, Masafumi;Matsuzaki, Masunori
• 通讯作者: Matsuzaki, Masunori

Mutation-linked Defective Domain Interaction within the Ryanodine Receptor Causes Ca2+ Leak Leading to Catecholaminergic Polymorphic Ventricular Tachycardia

Ryanodine 受体内突变相关的缺陷结构域相互作用导致 Ca2 泄漏，导致儿茶酚胺能多形性室性心动过速

• 发表时间: 2010
• 作者: Suetomi T;Yano M;Fukuda M;Hino A;Ono M;Xu X;Susa T;Uchinoumi H;Oda T;Okuda S;Kobayashi S;Yamamoto T;Ikeda Y;Matsuzaki M.
• 通讯作者: Matsuzaki M.

Decreased Affinity Of Calmodulin To RyR2 May Be A Sauce Mechanism Of Leaky Channel In CPVT-associated Mutation

钙调蛋白对 RyR2 的亲和力降低可能是 CPVT 相关突变中泄漏通道的酱料机制

• 发表时间: 2009
• 作者: Ogimoto A;et al.;Xiaojuan Xu
• 通讯作者: Xiaojuan Xu

Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia in a RyR2R2474S/+ Knock-In Mouse Model

• DOI: 10.1253/circj.cj-10-0680
• 发表时间: 2010-12-01
• 期刊: CIRCULATION JOURNAL
• 影响因子: 3.3
• 作者: Kobayashi, Shigeki;Yano, Masafumi;Matsuzaki, Masunori
• 通讯作者: Matsuzaki, Masunori

Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction.

钙调蛋白与心脏兰尼碱受体的结合缺陷在 CPVT 相关通道功能障碍中起着关键作用。

• 发表时间: 2010
• 期刊: Biochem Biophys Res Commun. 394
• 作者: Xu X;Yano M;Uchinoumi H;Hino A;Suetomi T;Ono M;Tateishi H;Oda T;Okuda S;Doi M;Kobayashi S;Yamamoto T;Ikeda Y;Ikemoto N;Matsuzaki M.
• 通讯作者: Matsuzaki M.