Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan.
Cardiovasc Res. 2012 Dec 1;96(3):433-43. doi: 10.1093/cvr/cvs271. Epub 2012 Aug 14.
The channel function of the cardiac ryanodine receptor (RyR2) is modulated by calmodulin (CaM). However, the involvement of CaM in aberrant Ca(2+) release in diseased hearts remains unclear. Here, we investigated the pathogenic role of defective CaM binding to the RyR2 in the channel dysfunction associated with heart failure.
The involvement of CaM in aberrant Ca(2+) release was assessed in normal and pacing-induced failing canine hearts. The apparent affinity of CaM for RyR2 was considerably lower in failing sarcoplasmic reticulum (SR) compared with normal SR. Thus, the amount of CaM bound to RyR2 was markedly decreased in failing myocytes. Expression of the CaM isoform Gly-Ser-His-CaM (GSH-CaM), which has much higher binding affinity than wild-type CaM for RyR1, restored normal CaM binding to RyR2 in both SR and myocytes of failing hearts. The Ca(2+) spark frequency (SpF) was markedly higher and the SR Ca(2+) content was lower in failing myocytes compared with normal myocytes. The incorporation of GSH-CaM into the failing myocytes corrected the aberrant SpF and SR Ca(2+) content to normal levels.
Reduced CaM binding to RyR2 seems to play a critical role in the pathogenesis of aberrant Ca(2+) release in failing hearts. Correction of the reduced CaM binding to RyR2 stabilizes the RyR2 channel function and thereby restores normal Ca(2+) handling and contractile function to failing hearts.
心脏兰尼碱受体（RyR2）的通道功能受钙调蛋白（CaM）调节。然而，CaM 在心衰相关疾病中异常 Ca²⁺释放中的作用仍不清楚。在此，我们研究了 RyR2 与 CaM 结合缺陷在心力衰竭相关通道功能障碍中的致病作用。
在正常和起搏诱导的衰竭犬心脏中评估 CaM 在异常 Ca²⁺释放中的作用。与正常 SR 相比，衰竭 SR 中 CaM 与 RyR2 的表观亲和力明显降低。因此，衰竭心肌细胞中与 RyR2 结合的 CaM 量显著减少。表达 CaM 同工型 Gly-Ser-His-CaM（GSH-CaM），其与 RyR1 的结合亲和力远高于野生型 CaM，可恢复衰竭心脏 SR 和心肌细胞中 RyR2 的正常 CaM 结合。与正常心肌细胞相比，衰竭心肌细胞的 Ca²⁺火花频率（SpF）明显更高，SR Ca²⁺含量更低。将 GSH-CaM 掺入衰竭心肌细胞可将异常 SpF 和 SR Ca²⁺含量校正至正常水平。
RyR2 与 CaM 的结合减少似乎在衰竭心脏异常 Ca²⁺释放的发病机制中起关键作用。校正 RyR2 与 CaM 的结合减少可稳定 RyR2 通道功能，从而使衰竭心脏恢复正常的 Ca²⁺处理和收缩功能。
