The calcium/calmodulin (Ca2+/CaM)-dependent protein kinase II (CaMKII) is activated through the binding of Ca2+/CaM to its regulatory domain and plays important roles in the nervous system and the heart. CaMKII activity is also increased under pro-oxidant conditions, so Erickson et al. investigated whether reactive oxygen species (ROS) might be involved. Exposure of purified CaMKII to hydrogen peroxide (H2O2) in the presence, but not absence, of Ca2+/CaM resulted in prolonged enzyme activity compared with that of untreated CaMKII. Ca2+/CaM-dependent autophosphorylation of Thr287 is known to prevent the reassociation of the enzyme’s autoinhibitory region with its catalytic domain and so enable prolonged enzyme activity. However, the effect of H2O2 on enzyme activity still occurred with a mutant form of CaMKII in which Thr287 was mutated to alanine. Mutation of Met281 and Met282 in the regulatory domain of CaMKII to valines blocked H2O2-dependent activation, although Thr287 autophosphorylation was unaffected. This suggests that Thr287 phosphorylation and Met281/Met282 oxidation are distinct mechanisms that lead to prolonged CaMKII activation in the presence of Ca2+/CaM. The authors developed an antibody against oxidized Met281/Met282 residues and found that the hormone angiotensin II (AngII) increased the abundance of oxidized CaMKII in the hearts of wild-type mice compared with that in untreated mice. AngII induced ROS production and apoptosis in treated cardiomyocytes, which was blocked when CaMKII was knocked down by short hairpin RNA. Finally, the abundance of oxidized CaMKII and the incidence of apoptotic cells were higher in the hearts of AngII-treated mice deficient in MsrA, an enzyme that reverses methionine oxidation, than in AngII-treated wild-type mice. As Griffith notes in commentary, the discovery that ROS directly activate CaMKII may help in our understanding of oxidant-dependent diseases of the heart and nervous system.
J. R. Erickson, M.-l. A. Joiner, X. Guan, W. Kutschke, J. Yang, C. V. Oddis, R. K. Bartlett, J. S. Lowe, S. E. O’Donnell, N. Aykin-Burns, M. C. Zimmerman, K. Zimmerman, A.-J. L. Ham, R. M. Weiss, D. R. Spitz, M. A. Shea, R. J. Colbran, P. J. Mohler, M. E. Anderson, A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 133, 462-474 (2008). [PubMed]
L. C. Griffith, CaMKII: New tricks for an old dog. Cell 133, 397-399 (2008). [PubMed]