A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation
A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation
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DOI：
10.1016/j.cell.2008.02.048
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发表时间：
2008-05-02
期刊：
影响因子：
64.5
通讯作者：
Anderson, Mark E.
中科院分区：
文献类型：
--
作者：
Erickson, Jeffrey R.;Joiner, Mei-ling A.;Anderson, Mark E.
钙/钙调蛋白（Ca 2 +/CaM）依赖性蛋白激酶II（CaMKII）偶联增加细胞内Ca 2+对可兴奋细胞的基本反应。CaMKII在20多年前通过对Ca 2 +/CaM的活化依赖性被鉴定，但最近的证据表明，CaMKII活性也通过促氧化条件增强。在这里，我们表明，成对的调节结构域蛋氨酸残基的氧化维持CaMKII活性的情况下，Ca 2 +/CaM。CaMK II被血管紧张素II（AngII）诱导的氧化激活，导致体外和体内心肌细胞凋亡。CaMKII氧化被甲硫氨酸亚砜还原酶A（MsrA）逆转，并且MsrA（-/-）小鼠表现出过度的CaMKII氧化和心肌细胞凋亡、心脏功能受损以及心肌梗死后死亡率增加。我们的数据表明了氧化激活CaMKII的动态机制，并强调了氧化依赖性CaMKII激活对AngII和缺血性心肌细胞凋亡的至关重要性。
Calcium/calmodulin (Ca2+/CaM)-dependent protein kinase II (CaMKII) couples increases in cellular Ca2+ to fundamental responses in excitable cells. CaMKII was identified over 20 years ago by activation dependence on Ca2+/CaM, but recent evidence shows that CaMKII activity is also enhanced by pro-oxidant conditions. Here we show that oxidation of paired regulatory domain methionine residues sustains CaMKII activity in the absence of Ca2+/CaM. CaMKII is activated by angiotensin II (AngII)-induced oxidation, leading to apoptosis in cardiomyocytes both in vitro and in vivo. CaMKII oxidation is reversed by methionine sulfoxide reductase A (MsrA), and MsrA(-/-) mice show exaggerated CaMKII oxidation and myocardial apoptosis, impaired cardiac function, and increased mortality after myocardial infarction. Our data demonstrate a dynamic mechanism for CaMKII activation by oxidation and highlight the critical importance of oxidation-dependent CaMKII activation to AngII and ischemic myocardial apoptosis.