Department of Pharmacology, University of California at Davis, Davis, California 95616, USA.
Physiol Rev. 2011 Jul;91(3):889-915. doi: 10.1152/physrev.00018.2010.
The multifunctional Ca(2+)- and calmodulin-dependent protein kinase II (CaMKII) is now recognized to play a central role in pathological events in the cardiovascular system. CaMKII has diverse downstream targets that promote vascular disease, heart failure, and arrhythmias, so improved understanding of CaMKII signaling has the potential to lead to new therapies for cardiovascular disease. CaMKII is a multimeric serine-threonine kinase that is initially activated by binding calcified calmodulin (Ca(2+)/CaM). Under conditions of sustained exposure to elevated Ca(2+)/CaM, CaMKII transitions into a Ca(2+)/CaM-autonomous enzyme by two distinct but parallel processes. Autophosphorylation of threonine-287 in the CaMKII regulatory domain "traps" CaMKII into an open configuration even after Ca(2+)/CaM unbinding. More recently, our group identified a pair of methionines (281/282) in the CaMKII regulatory domain that undergo a partially reversible oxidation which, like autophosphorylation, prevents CaMKII from inactivating after Ca(2+)/CaM unbinding. Here we review roles of CaMKII in cardiovascular disease with an eye to understanding how CaMKII may act as a transduction signal to connect pro-oxidant conditions into specific downstream pathological effects that are relevant to rare and common forms of cardiovascular disease.
多功能 Ca(2+)-和钙调蛋白依赖性蛋白激酶 II（CaMKII）现在被认为在心血管系统的病理事件中发挥核心作用。CaMKII 有多种下游靶标，可促进血管疾病、心力衰竭和心律失常，因此，对 CaMKII 信号转导的深入了解有可能为心血管疾病带来新的治疗方法。CaMKII 是一种多聚丝氨酸-苏氨酸激酶，最初通过与钙结合钙调蛋白（Ca(2+)/CaM）激活。在持续暴露于升高的 Ca(2+)/CaM 的条件下，CaMKII 通过两个不同但平行的过程转变为 Ca(2+)/CaM 自主酶。CaMKII 调节域中苏氨酸-287 的自身磷酸化“捕获”CaMKII 处于开放构象，即使在 Ca(2+)/CaM 解结合后也是如此。最近，我们小组在 CaMKII 调节域中鉴定出一对蛋氨酸（281/282），它们经历部分可逆氧化，与自身磷酸化一样，可防止 CaMKII 在 Ca(2+)/CaM 解结合后失活。在这里，我们回顾了 CaMKII 在心血管疾病中的作用，以期了解 CaMKII 如何作为转导信号，将促氧化剂条件连接到与罕见和常见形式的心血管疾病相关的特定下游病理效应。
