Regulation of cardiac calcium signaling by newly identified calcium pump modulators.
Regulation of cardiac calcium signaling by newly identified calcium pump modulators.
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新发现的钙泵调节剂对心脏钙信号的调节。
DOI：
10.1016/j.bbrc.2023.149136
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发表时间：
2023
影响因子：
3.1
通讯作者：
Zima,AlekseyV
中科院分区：
文献类型：
--
作者：
Bovo,Elisa;Rebbeck,RobynT;Roopnarine,Osha;Cornea,RazvanL;Thomas,DavidD;Zima,AlekseyV
在心肌细胞中，肌浆网/内质网钙-ATPase(SERCA2a)是细胞内钙调节的中心组成部分。一些心脏疾病，包括心力衰竭，与SERCA2a下调导致的心肌收缩减少有关。因此，开发能够改善SERCA2a功能的新药的必要性很高。我们最近从我们的筛选活动中发现了SERCA2a调节剂(化合物6和8)，并证实了生化SERCA2a ATPase活性和钙摄取活性的激活。本研究利用共聚焦显微镜和细胞内钙成像技术研究了这些SERCA2a激动剂对小鼠心室肌细胞钙调节和表达人SERCA2a的HEK293细胞内质网钙摄取的影响。心肌细胞内钙动力学分析表明，化合物6和8均可增加动作电位引起的钙瞬变和肌浆网钙负荷。化合物6对L钙通道电流触发的钙瞬变的影响可忽略不计，而化合物8增加了钙通道激活过程中的钙瞬变，提示化合物8存在非靶点的蛋白质相互作用。对人SERCA2a对HEK细胞内质网钙转运的分析表明，只有化合物6显著增加ER钙摄取和ER钙负荷，而化合物8对SERCA2a钙转运无明显影响。这项研究表明，化合物6具有良好的特性，可以通过选择性地增强SERCA2a对钙的摄取来改善细胞内钙动力学。
In cardiomyocytes, the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) is a central component of intracellular Ca2+regulation. Several heart diseases, including heart failure, are associated with reduced myocardial contraction due to SERCA2a downregulation. Therefore, the need for developing new drugs that could improve SERCA2a function is high. We have recently identified SERCA2a modulators (Compounds 6 and 8) from our screening campaigns and confirmed activation of biochemical SERCA2a ATPase activity and Ca2+uptake activity. In this study, confocal microscopy and in-cell Ca2+imaging were used to characterize the effects of these SERCA2a activators on Ca2+regulation in mouse ventricular myocytes and endoplasmic reticulum (ER) Ca2+uptake in a HEK293 cell expressing human SERCA2a. Analysis of cytosolic Ca2+dynamics in cardiomyocytes revealed that both Compounds (6 and 8) increase the action potential-induced Ca2+transients and sarcoplasmic reticulum (SR) Ca2+load. While Compound 6 induced a negligible effect on Ca2+transients invoked by the L-type Ca2+channel (LTCC) current, Compound 8 increased Ca2+transients during LTCC activation, suggesting an off-target protein interaction of Compound 8. Analysis of ER Ca2+transport by human SERCA2a in HEK cells showed that only Compound 6 increased both ER Ca2+uptake and ER Ca2+load significantly, whereas Compound 8 had no effect on SERCA2a Ca2+transport. This study revealed that Compound 6 exhibits promising characteristics that can improve intracellular Ca2+dynamics by selectively enhancing SERCA2a Ca2+uptake.