Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor.
Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor.
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DOI：
10.1016/j.jacc.2009.01.065
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发表时间：
2009-05-26
影响因子：
24
通讯作者：
Matsuzaki, Masunori
中科院分区：
文献类型：
--
作者：
Kobayashi, Shigeki;Yano, Masafumi;Suetomi, Takeshi;Ono, Makoto;Tateishi, Hiroki;Mochizuki, Mamoru;Xu, Xiaojuan;Uchinoumi, Hitoshi;Okuda, Shinichi;Yamamoto, Takeshi;Koseki, Noritaka;Kyushiki, Hiroyuki;Ikemoto, Noriaki;Matsuzaki, Masunori
旨在研究丹曲林（一种通常用于治疗恶性高热 (MH) 的药物）对衰竭心脏中 Ca2+ 释放和心肌细胞功能的影响。兰尼碱受体 (RyR) 的 N 端 (N: 1-600) 和中央 (C: 2000-2500) 结构域含有许多与骨骼肌 RyR (RyR1) 中的 MH 和心脏 RyR (RyR2) 中的多形性室性心动过速相关的突变。有强有力的证据表明这些区域之间的域间相互作用在通道调节机制中发挥着重要作用。从狗左心室肌肉中分离肌浆网 (SR) 囊泡和心肌细胞（正常或快速心室起搏 4 周），用于 Ca2+ 渗漏、瞬态和火花测定。为了评估相互作用结构域的压缩或解压缩状态，RyR 以定点方式用甲基香豆素乙酸酯进行荧光标记。我们采用石英晶体微天平技术来识别 RyR2 内的丹曲林结合位点。 Dantrolene 特异性结合 RyR2 中的结构域 601-620。在从起搏引起的狗衰竭心脏中分离出的 SR 中，已经发生了有缺陷的域间相互作用（域解压缩），导致自发的 Ca2+ 泄漏。丹曲林抑制结构域解链和 Ca2+ 泄漏，显示出相同的药物浓度依赖性 (IC50=0.3 μmol/L)。在衰竭的心肌细胞中，经常观察到舒张期 Ca2+ 火花和延迟后除极，但 1 μmol/L 丹曲林抑制这两种事件。 Dantrolene 可纠正衰竭心脏中 RyR2 内有缺陷的域间相互作用，抑制自发 Ca2+ 渗漏，进而改善衰竭心脏中的心肌细胞功能。因此，丹曲林可能具有治疗心力衰竭的潜力，特别是针对 RyR2。
To investigate the effect of dantrolene, a drug generally used to treat Malignant Hyperthermia (MH), on the Ca2+ release and cardiomyocyte function in failing hearts. The N-terminal (N: 1-600) and Central (C: 2000-2500) domains of the ryanodine receptor (RyR), harbor many mutations associated with MH in skeletal muscle RyR (RyR1) and polymorphic ventricular tachycardia in cardiac RyR (RyR2). There is strong evidence that inter-domain interaction between these regions plays an important role in the mechanism of channel regulation. Sarcoplasmic reticulum (SR) vesicles and cardiomyocytes were isolated from dog LV muscles (normal or rapid ventricular pacing for 4 weeks), for Ca2+ leak, transient, and spark assays. To assess the zipped or unzipped state of the interacting domains, the RyR was fluorescently labeled with methylcoumarin acetate in a site-directed manner. We employed a quartz-crystal microbalance technique to identify the dantrolene binding site within the RyR2. Dantrolene specifically bound to domain 601-620 in RyR2. In the SR isolated from pacing-induced dog failing hearts, the defective inter-domain interaction_(domain unzipping) has already occurred, causing spontaneous Ca2+ leak. Dantrolene suppressed both domain unzipping and the Ca2+ leak, showing identical drug concentration-dependence (IC50=0.3 μmol/L). In failing cardiomyocytes, both diastolic Ca2+ sparks and delayed afterdepolarization were frequently observed, but 1 μmol/L dantrolene inhibited both events. Dantrolene corrects defective inter-domain interactions within RyR2 in failing hearts, inhibits spontaneous Ca2+ leak, in turn improves cardiomyocyte function in failing hearts. Thus, dantrolene may have a potential to treat heart failure, specifically targeting the RyR2.
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