Mattiazzi Alicia, Bassani Rosana A, Escobar Ariel L, Palomeque Julieta, Valverde Carlos A, Vila Petroff Martín, Bers Donald M
Centro de Investigaciones Cardiovasculares, The National Scientific and Technical Research Council-La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina;
Centro de Engenharia Biomédica, Universidade Estadual de Campinas, Campinas, SP, Brazil;
Am J Physiol Heart Circ Physiol. 2015 May 15;308(10):H1177-91. doi: 10.1152/ajpheart.00007.2015. Epub 2015 Mar 6.
Calcium dynamics is central in cardiac physiology, as the key event leading to the excitation-contraction coupling (ECC) and relaxation processes. The primary function of Ca(2+) in the heart is the control of mechanical activity developed by the myofibril contractile apparatus. This key role of Ca(2+) signaling explains the subtle and critical control of important events of ECC and relaxation, such as Ca(2+) influx and SR Ca(2+) release and uptake. The multifunctional Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a signaling molecule that regulates a diverse array of proteins involved not only in ECC and relaxation but also in cell death, transcriptional activation of hypertrophy, inflammation, and arrhythmias. CaMKII activity is triggered by an increase in intracellular Ca(2+) levels. This activity can be sustained, creating molecular memory after the decline in Ca(2+) concentration, by autophosphorylation of the enzyme, as well as by oxidation, glycosylation, and nitrosylation at different sites of the regulatory domain of the kinase. CaMKII activity is enhanced in several cardiac diseases, altering the signaling pathways by which CaMKII regulates the different fundamental proteins involved in functional and transcriptional cardiac processes. Dysregulation of these pathways constitutes a central mechanism of various cardiac disease phenomena, like apoptosis and necrosis during ischemia/reperfusion injury, digitalis exposure, post-acidosis and heart failure arrhythmias, or cardiac hypertrophy. Here we summarize significant aspects of the molecular physiology of CaMKII and provide a conceptual framework for understanding the role of the CaMKII cascade on Ca(2+) regulation and dysregulation in cardiac health and disease.
钙动力学在心脏生理学中至关重要，是导致兴奋-收缩偶联（ECC）和舒张过程的关键事件。Ca(2+)在心脏中的主要功能是控制肌原纤维收缩装置产生的机械活动。Ca(2+)信号的这一关键作用解释了对ECC和舒张等重要事件的微妙而关键的控制，如Ca(2+)内流以及肌浆网Ca(2+)的释放和摄取。多功能的钙/钙调蛋白依赖性蛋白激酶II（CaMKII）是一种信号分子，它调节多种蛋白质，这些蛋白质不仅参与ECC和舒张，还涉及细胞死亡、肥大的转录激活、炎症和心律失常。CaMKII的活性由细胞内Ca(2+)水平的升高触发。这种活性可以持续存在，在Ca(2+)浓度下降后通过酶的自身磷酸化以及激酶调节域不同位点的氧化、糖基化和亚硝基化形成分子记忆。CaMKII的活性在几种心脏疾病中增强，改变了CaMKII调节参与心脏功能和转录过程的不同基础蛋白质的信号通路。这些信号通路的失调构成了各种心脏疾病现象的核心机制，如缺血/再灌注损伤、洋地黄暴露、酸中毒后和心力衰竭心律失常期间的细胞凋亡和坏死，或心脏肥大。在此，我们总结了CaMKII分子生理学的重要方面，并提供了一个概念框架，以理解CaMKII级联在心脏健康和疾病中对Ca(2+)调节和失调的作用。
