A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine Oxidation

Jeffrey R. Erickson, Mei ling A. Joiner, Xiaoqun Guan, William Kutschke, Jinying Yang, Carmine V. Oddis, Ryan K. Bartlett, John S. Lowe, Susan E. O'Donnell, Nukhet Aykin-Burns, Matthew C. Zimmerman, Kathy Zimmerman, Amy Joan L. Ham, Robert M. Weiss, Douglas R. Spitz, Madeline A. Shea, Roger J. Colbran, Peter J. Mohler, Mark E. Anderson

Research output: Contribution to journalArticle

658 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)462-474
Number of pages13
JournalCell
Volume133
Issue number3
DOIs
StatePublished - May 2 2008

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Keywords

  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Erickson, J. R., Joiner, M. L. A., Guan, X., Kutschke, W., Yang, J., Oddis, C. V., Bartlett, R. K., Lowe, J. S., O'Donnell, S. E., Aykin-Burns, N., Zimmerman, M. C., Zimmerman, K., Ham, A. J. L., Weiss, R. M., Spitz, D. R., Shea, M. A., Colbran, R. J., Mohler, P. J., & Anderson, M. E. (2008). A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine Oxidation. Cell, 133(3), 462-474. https://doi.org/10.1016/j.cell.2008.02.048