A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation.
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.
Erickson
Jeffrey R
JR
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1109, USA.
Joiner
Mei-ling A
ML
Guan
Xiaoqun
X
Kutschke
William
W
Yang
Jinying
J
Oddis
Carmine V
CV
Bartlett
Ryan K
RK
Lowe
John S
JS
O'Donnell
Susan E
SE
Aykin-Burns
Nukhet
N
Zimmerman
Matthew C
MC
Zimmerman
Kathy
K
Ham
Amy-Joan L
AJ
Weiss
Robert M
RM
Spitz
Douglas R
DR
Shea
Madeline A
MA
Colbran
Roger J
RJ
Mohler
Peter J
PJ
Anderson
Mark E
ME
D000804:Angiotensin II; D000818:Animals; D017209:Apoptosis; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D006331:Heart Diseases / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism*; D051150:Methionine Sulfoxide Reductases; D051379:Mice; D016297:Mutagenesis, Site-Directed; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D002147:Calmodulin; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D008715:Methionine; D010088:Oxidoreductases; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium