Role of CaMKII in cardiac arrhythmias.
Role of CaMKII in cardiac arrhythmias.
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DOI：
10.1016/j.tcm.2014.12.001
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发表时间：
2015-07
影响因子：
9.3
通讯作者：
Mohler, Peter J.
中科院分区：
文献类型：
--
作者：
Hund, Thomas J.;Mohler, Peter J.
蛋白质磷酸化是脊椎动物信号调节的中心机制。就心血管系统而言，肌细胞靶点的磷酸化对于兴奋收缩偶联、代谢、细胞内钙调节、线粒体活性、转录调节和细胞骨架动力学的调节至关重要。事实上，在过去的60年里，调节蛋白激酶信号的途径一直是心血管治疗的主要途径。钙/钙调素依赖性蛋白激酶II （CaMKII）是一种多功能丝氨酸/苏氨酸激酶，在人体生理中具有多种作用。基于CaMKII的信号功能障碍与许多心血管表型相关，包括心力衰竭和心律失常，并且CaMKII水平在人类和动物心脏病疾病模型中升高。虽然近十年来人们一直致力于将CaMKII作为治疗心力衰竭和心律失常表型的靶点，但迄今为止，以CaMKII分子为靶点的抗心律失常效果尚未取得成功，原因尚不完全清楚，尽管(1)缺乏化合物特异性，(2)众多下游靶点可能是促成因素。这篇综述将提供CaMKII调控的当前通路的最新进展，目的是阐明可能被调节的上游调控机制和下游靶点，以预防心脏电缺陷。虽然该综述将涵盖心血管疾病中CaMKII功能障碍的多个方面，但我们特别关注CaMKII相关的晚期Na+电流作为心律失常的新治疗靶点的潜力。
Protein phosphorylation is a central mechanism in vertebrates for the regulation of signaling. With regard to the cardiovascular system, phosphorylation of myocyte targets is critical for the regulation of excitation contraction coupling, metabolism, intracellular calcium regulation, mitochondrial activity, transcriptional regulation, and cytoskeletal dynamics. In fact, pathways that tune protein kinase signaling have been a mainstay for cardiovascular therapies for the past 60 years. The calcium/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase with numerous roles in human physiology. Dysfunction in CaMKII-based signaling has been linked with a host of cardiovascular phenotypes including heart failure and arrhythmia, and CaMKII levels are elevated in human and animal disease models of heart disease. While nearly a decade has been invested in targeting CaMKII for the treatment of heart failure and arrhythmia phenotypes, to date, approaches to target the molecule for antiarrhythmic benefit have been unsuccessful for reasons that are still not entirely clear, although (1) lack of compound specificity and (2) the multitude of downstream targets are likely contributing factors. This review will provide an update on current pathways regulated by CaMKII with the goal of illustrating potential upstream regulatory mechanisms and downstream targets that may be modulated for the prevention of cardiac electrical defects. While the review will cover multiple aspects of CaMKII dysfunction in cardiovascular disease, we have given special attention to the potential of CaMKII-associated late Na+ current as a novel therapeutic target for cardiac arrhythmia.
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影响因子：
37.8
作者：
Koval OM;Snyder JS;Wolf RM;Pavlovicz RE;Glynn P;Curran J;Leymaster ND;Dun W;Wright PJ;Cardona N;Qian L;Mitchell CC;Boyden PA;Binkley PF;Li C;Anderson ME;Mohler PJ;Hund TJ
通讯作者：
Hund TJ
影响因子：
5.6
作者：
Bers DM;Morotti S
通讯作者：
Morotti S
影响因子：
20.1
作者：
Gavillet, Bruno;Rougier, Jean-Sebastien;Abriel, Hugues
通讯作者：
Abriel, Hugues
影响因子：
64.5
作者：
Erickson, Jeffrey R.;Joiner, Mei-ling A.;Anderson, Mark E.
通讯作者：
Anderson, Mark E.
DOI：
10.1098/rsta.2006.1758
发表时间：
2006-05-15
影响因子：
5
作者：
Iribe, G;Kohl, P;Noble, D
通讯作者：
Noble, D