Fixing ryanodine receptor Ca leak - a novel therapeutic strategy for contractile failure in heart and skeletal muscle.
Fixing ryanodine receptor Ca leak - a novel therapeutic strategy for contractile failure in heart and skeletal muscle.
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DOI：
10.1016/j.ddmec.2010.09.009
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Marks, Andrew R
中科院分区：
文献类型：
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作者：
Andersson, Daniel C;Marks, Andrew R
在调节心肌和骨骼肌收缩性中的关键组分是经由肌浆网（SR）中的兰尼碱受体（RyR）Ca 2+释放通道释放Ca 2+。在心力衰竭和肌病中，发现RyR过度磷酸化或亚硝基化，并耗尽RyR稳定蛋白钙稳定蛋白（FK 506结合蛋白12/12.6）。RyR通道复合物的这种重构导致细胞内SR Ca 2+渗漏和收缩性受损。尽管心力衰竭治疗取得了最新进展，但这种疾病的死亡率仍然非常高。此外，用于肌无力和肌病的药物治疗几乎不存在。一类新的RyR稳定药物rycals，由于保留RyR-钙稳定蛋白相互作用，通过稳定RyR通道来减少Ca 2+泄漏，最近已被证明可以改善心脏和骨骼肌的收缩功能。这为治疗心脏和骨骼肌收缩衰竭开辟了一种新的治疗策略。
A critical component in regulating cardiac and skeletal muscle contractility is the release of Ca2+ via ryanodine receptor (RyR) Ca2+ release channels in the sarcoplasmic reticulum (SR). In heart failure and myopathy, the RyR has been found to be excessively phosphorylated or nitrosylated and depleted of the RyR-stabilizing protein calstabin (FK506 binding protein 12/12.6). This remodeling of the RyR channel complex results in an intracellular SR Ca2+ leak and impaired contractility. Despite recent advances in heart failure treatment, there are still devastatingly high mortality rates with this disease. Moreover, pharmacological treatment for muscle weakness and myopathy is nearly nonexistent. A novel class of RyR-stabilizing drugs, rycals, which reduce Ca2+ leak by stabilizing the RyR channels due to preservation of the RyR-calstabin interaction, have recently been shown to improve contractile function in both heart and skeletal muscle. This opens up a novel therapeutic strategy for the treatment of contractile failure in the cardiac and skeletal muscle.