Succinate modulates Ca2+ transient and cardiomyocyte viability through PKA-dependent pathway
Succinate modulates Ca2+ transient and cardiomyocyte viability through PKA-dependent pathway
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DOI：
10.1016/j.ceca.2009.11.003
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发表时间：
2010-01-01
期刊：
影响因子：
4
通讯作者：
Leite, M. Fatima
中科院分区：
文献类型：
--
作者：
Aguiar, Carla J.;Andrade, Vanessa L.;Leite, M. Fatima
GPR 91是一种孤儿G蛋白偶联受体（GPCR），在几种组织中被表征为琥珀酸（柠檬酸循环中间体）的受体。在心脏中，琥珀酸的作用是未知的。我们现在报告，大鼠心室心肌细胞表达GPR 91。我们发现，琥珀酸，通过GPR 91，通过增加磷酸化水平的ryanodine受体和受磷蛋白，两个众所周知的Ca 2+处理蛋白，增加全球Ca 2+瞬变的幅度和下降速率。用腺苷酸环化酶和cAMP依赖性蛋白激酶（PKA）抑制剂预处理可消除琥珀酸对钙瞬变的影响。使用基于FRET的A-激酶活性报告基因进一步证实了琥珀酸对PKA的直接激活。此外，琥珀酸通过半胱天冬酶-3活化途径降低心肌细胞活力，PKA抑制也能阻止这种作用。综上所述，这些观察结果表明，琥珀酸作为心肌细胞中的信号分子，通过PKA依赖性途径调节全局Ca 2+瞬变和细胞活力。(C)2009爱思唯尔有限公司保留所有权利。
GPR91 is an orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate, a citric acid cycle intermediate, in several tissues. In the heart, the role of succinate is unknown. We now report that rat ventricular cardiomyocytes express GPR91. We found that succinate, through GPR91, increases the amplitude and the rate of decline of global Ca2+ transient, by increasing the phosphorylation levels of ryanodine receptor and phospholamban, two well known Ca2+ handling proteins. The effects of succinate on Ca2+ transient were abolished by pre-treatment with adenylyl cyclase and cAMP-dependent protein kinase (PKA) inhibitors. Direct PKA activation by succinate was further confirmed using a FRET-based A-kinase activity reporter. Additionally, succinate decreases cardiomyocyte viability through a caspase-3 activation pathway, effect also prevented by PKA inhibition. Taken together, these observations show that succinate acts as a signaling molecule in cardiomyocytes, modulating global Ca2+ transient and cell viability through a PKA-dependent pathway. (C) 2009 Elsevier Ltd. All rights reserved.