title: A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation.
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.
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1109, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Erickson
authors.forename: Mei-ling A
authors.initials: ML
authors.lastname: Joiner
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Guan
authors.forename: William
authors.initials: W
authors.lastname: Kutschke
authors.forename: Jinying
authors.initials: J
authors.lastname: Yang
authors.forename: Carmine V
authors.initials: CV
authors.lastname: Oddis
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Bartlett
authors.forename: John S
authors.initials: JS
authors.lastname: Lowe
authors.forename: Susan E
authors.initials: SE
authors.lastname: O'Donnell
authors.forename: Nukhet
authors.initials: N
authors.lastname: Aykin-Burns
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Zimmerman
authors.forename: Kathy
authors.initials: K
authors.lastname: Zimmerman
authors.forename: Amy-Joan L
authors.initials: AJ
authors.lastname: Ham
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.forename: Madeline A
authors.initials: MA
authors.lastname: Shea
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: 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
chemical_list: 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