Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome.
Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome.
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DOI：
10.1161/circresaha.111.259754
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发表时间：
2012-06-08
影响因子：
20.1
通讯作者：
Hajjar RJ
中科院分区：
文献类型：
--
作者：
Kranias EG;Hajjar RJ
心脏病仍然是西方世界死亡和残疾的主要原因。目前的疗法旨在治疗症状，而不是治疗心力衰竭病因和病理重塑的亚细胞机制。导致人类和实验性衰竭心脏收缩性能下降的一个普遍特征是肌浆网 (SR) 中的钙隔离受损。 SR 钙摄取由 Ca2+-ATP 酶 (SERCA2) 介导，其活性受磷蛋白 (PLN) 可逆调节。去磷酸化的 PLN 是 SERCA 的抑制剂，而 PLN 的磷酸化可以缓解这种抑制。然而，我们最近鉴定出 SUMO、S100 和富含组氨酸的 Ca 结合蛋白作为 SERCA 活性的调节剂，改变了最初对 PLN/SERCA 调节复合物的简单看法。此外，PLN 活性受到两种磷蛋白的调节，即蛋白磷酸酶 1 的抑制剂 1 和小热休克蛋白 20，这会影响整体 SERCA 介导的 Ca 转运。本综述将重点介绍多聚体 SERCA/PLN 整体的心肌收缩力调节机制，以及通过使用小分子和基因转移方法针对该复合物的新治疗途径的潜力。
Heart disease remains the leading cause of death and disability in the Western world. Current therapies aim at treating the symptoms rather than the subcellular mechanisms, underlying the etiology and pathological remodeling in heart failure. A universal characteristic, contributing to the decreased contractile performance in human and experimental failing hearts, is impaired calcium sequestration into the sarcoplasmic reticulum (SR). SR calcium uptake is mediated by a Ca2+-ATPase (SERCA2), whose activity is reversibly regulated by phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA and phosphorylation of PLN relieves this inhibition. However, the initial simple view of a PLN/SERCA regulatory complex has been modified by our recent identification of SUMO, S100 and the histidine rich Ca-binding protein as regulators of SERCA activity. In addition, PLN activity is regulated by two phosphoproteins, the inhibitor-1 of protein phosphatase 1 and the small heat shock protein 20, which impact the overall SERCA-mediated Ca-transport. This review will highlight the regulatory mechanisms of cardiac contractility by the multimeric SERCA/PLN-ensemble and the potential for new therapeutic avenues targeting this complex by using small molecules and gene transfer methods.