Niggli Ernst, Ullrich Nina D, Gutierrez Daniel, Kyrychenko Sergii, Poláková Eva, Shirokova Natalia
Department of Physiology, University of Bern, Bern, Switzerland.
Biochim Biophys Acta. 2013 Apr;1833(4):866-75. doi: 10.1016/j.bbamcr.2012.08.016. Epub 2012 Aug 31.
In cardiac muscle, a number of posttranslational protein modifications can alter the function of the Ca(2+) release channel of the sarcoplasmic reticulum (SR), also known as the ryanodine receptor (RyR). During every heartbeat RyRs are activated by the Ca(2+)-induced Ca(2+) release mechanism and contribute a large fraction of the Ca(2+) required for contraction. Some of the posttranslational modifications of the RyR are known to affect its gating and Ca(2+) sensitivity. Presently, research in a number of laboratories is focused on RyR phosphorylation, both by PKA and CaMKII, or on RyR modifications caused by reactive oxygen and nitrogen species (ROS/RNS). Both classes of posttranslational modifications are thought to play important roles in the physiological regulation of channel activity, but are also known to provoke abnormal alterations during various diseases. Only recently it was realized that several types of posttranslational modifications are tightly connected and form synergistic (or antagonistic) feed-back loops resulting in additive and potentially detrimental downstream effects. This review summarizes recent findings on such posttranslational modifications, attempts to bridge molecular with cellular findings, and opens a perspective for future work trying to understand the ramifications of crosstalk in these multiple signaling pathways. Clarifying these complex interactions will be important in the development of novel therapeutic approaches, since this may form the foundation for the implementation of multi-pronged treatment regimes in the future. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction.
在心肌中，许多翻译后蛋白质修饰可改变肌浆网（SR）的Ca(2+)释放通道的功能，该通道也称为雷诺丁受体（RyR）。在每次心跳过程中，RyRs通过Ca(2+)诱导的Ca(2+)释放机制被激活，并为收缩所需的大部分Ca(2+)做出贡献。已知RyR的一些翻译后修饰会影响其门控和Ca(2+)敏感性。目前，许多实验室的研究集中在PKA和CaMKII对RyR的磷酸化，或活性氧和氮物种（ROS/RNS）引起的RyR修饰。这两类翻译后修饰都被认为在通道活性的生理调节中起重要作用，但也已知在各种疾病期间会引发异常改变。直到最近才意识到，几种类型的翻译后修饰紧密相连，形成协同（或拮抗）反馈环，导致累加和潜在有害的下游效应。本综述总结了关于此类翻译后修饰的最新发现，试图将分子层面的发现与细胞层面的发现联系起来，并为未来的研究开辟一个视角，以了解这些多重信号通路中串扰的影响。阐明这些复杂的相互作用对于开发新的治疗方法很重要，因为这可能为未来实施多管齐下的治疗方案奠定基础。本文是名为：心肌细胞生物学：心脏分化、代谢和收缩途径的特刊的一部分。
