Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure
Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure
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DOI：
10.1093/cvr/cvq108
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发表时间：
2010-09-01
影响因子：
10.8
通讯作者：
Matsuzaki, Masunori
中科院分区：
文献类型：
--
作者：
Ono, Makoto;Yano, Masafumi;Matsuzaki, Masunori
钙调素（CaM）是众所周知的调节心脏兰尼碱受体（RyR 2）的通道功能。然而，钙调素在病变心脏异常钙释放中的可能作用尚不清楚。本研究旨在探讨起搏诱导的衰竭心脏中RyR 2结合的钙调素（CaM）的状态和通道功能障碍，并在正常和衰竭犬心脏中评估CaM与RyR 2结合的特征以及CaM在异常Ca 2+释放中的作用。钙调素结合RyR 2的亲和力低于失败的肌浆网（SR）比在正常SR。此外，FK 506，FKBP12.6从RyR 2解离，正常SR降低钙调素结合亲和力。丹曲林恢复了正常水平的钙调素结合亲和力，无论是在FK 506处理（正常）SR或失败的SR，这表明有缺陷的N-末端结构域和RyR 2（丹曲林的治疗靶点）的中央结构域之间的相互作用是在失败的心脏钙调素结合亲和力的降低。在皂苷透化的心肌细胞中，失败的心肌细胞中自发性Ca 2+火花的频率比正常心肌细胞中的自发性Ca 2+火花的频率增加得多，而添加高浓度的CaM减弱了Ca 2+火花的异常增加。RyR 2内N-末端和中心结构域之间的缺陷性结构域间相互作用降低了CaM与RyR 2的结合亲和力，从而引起衰竭心脏中的自发性Ca 2+释放事件。纠正钙调素结合缺陷可能是一种新的策略，以防止异常的钙释放在心力衰竭。
Calmodulin (CaM) is well known to modulate the channel function of the cardiac ryanodine receptor (RyR2). However, the possible role of CaM on the aberrant Ca2+ release in diseased hearts remains unclear. In this study, we investigated the state of RyR2-bound CaM and channel dysfunctions in pacing-induced failing hearts.The characteristics of CaM binding to RyR2 and the role of CaM on the aberrant Ca2+ release were assessed in normal and failing canine hearts. The affinity of CaM binding to RyR2 was lower in failing sarcoplasmic reticulum (SR) than in normal SR. Addition of FK506, which dissociates FKBP12.6 from RyR2, to normal SR reduced the CaM-binding affinity. Dantrolene restored a normal level of the CaM-binding affinity in either FK506-treated (normal) SR or failing SR, suggesting that the defective inter-domain interaction between the N-terminal domain and the central domain of RyR2 (the therapeutic target of dantrolene) is involved in the reduction of the CaM-binding affinity in failing hearts. In saponin-permeabilized cardiomyocytes, the frequency of spontaneous Ca2+ sparks was much more increased in failing cardiomyocytes than in normal cardiomyocytes, whereas the addition of a high concentration of CaM attenuated the aberrant increase of Ca2+ sparks.The defective inter-domain interaction between N-terminal and central domains within RyR2 reduces the binding affinity of CaM to RyR2, thereby causing the spontaneous Ca2+ release events in failing hearts. Correction of the defective CaM binding may be a new strategy to protect against the aberrant Ca2+ release in heart failure.