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Cell. 2008 May 2;133(3):462-74. doi: 10.1016/j.cell.2008.02.048.

A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation.

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  • 1Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1109, USA.

Abstract

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.

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PMID:
18455987
[PubMed - indexed for MEDLINE]
PMCID:
PMC2435269
Free PMC Article

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