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Colbran Lab

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

AUTHORS

Erickson JRJeffrey R , Joiner ML Mei-ling A , Guan X Xiaoqun , Kutschke W William , Yang J Jinying , Oddis CV Carmine V , Bartlett RK Ryan K , Lowe JS John S , O'Donnell SE Susan E , Aykin-Burns N Nukhet , Zimmerman MC Matthew C , Zimmerman K Kathy , Ham AJ Amy-Joan L , Weiss RM Robert M , Spitz DR Douglas R , Shea MA Madeline A , Colbran RJ Roger J , Mohler PJ Peter J , Anderson ME Mark E . Cell. 2008 5 2; 133(3). 462-74

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.