title: Ischemia-elicited oxidative modulation of Ca2+/calmodulin-dependent protein kinase II.
abstract: Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) plays a critical role in neuronal signal transduction and synaptic plasticity. Here, we showed that this kinase was very susceptible to oxidative modulation. Treatment of mouse brain synaptosomes with H2O2, diamide, and sodium nitroprusside caused aggregation of CaMKII through formation of disulfide and non-disulfide linkages, and partial inhibition of the kinase activity. These CaMKII aggregates were found to associate with the post synaptic density. However, treatment of purified CaMKII with these oxidants did not replicate those effects observed in the synaptosomes. Using two previously identified potential mediators of oxidants in the brain, glutathione disulfide S-monoxide (GS-DSMO) and glutathione disulfide S-dioxide (GS-DSDO), we showed that they oxidized and inhibited CaMKII in a manner partly related to those of the oxidant-treated synaptosomes as well as the ischemia-elicited oxidative stress in the acutely prepared hippocampal slices. Interestingly, the autophosphorylated and activated CaMKII was relatively refractory to GS-DSMO- and GS-DSDO-mediated aggregation. Short term ischemia (10 min) caused a depression of basal synaptic response of the hippocampal slices, and re-oxygenation (after 10 min) reversed the depression. However, oxidation of CaMKII remained at above the pre-ischemic level throughout the treatment. Oxidation of CaMKII also prevented full recovery of CaMKII autophosphorylation after re-oxygenation. Subsequently, the high frequency stimulation-mediated synaptic potentiation in the hippocampal CA1 region was significantly reduced compared with the control without ischemia. Thus, ischemia-evoked oxidation of CaMKII, probably via the action of glutathione disulfide S-oxides or their analogues, may be involved in the suppression of synaptic plasticity.
authors.affiliation: Developmental Neurobiology Program, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Shetty
authors.forename: Freesia L
authors.initials: FL
authors.lastname: Huang
authors.forename: Kuo-Ping
authors.initials: KP
authors.lastname: Huang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D019803:Glutathione Disulfide / Q000031:analogs & derivatives* / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects; D016877:Oxidants / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013574:Synaptosomes / Q000201:enzymology* / Q000473:pathology
chemical_list: D004220:Disulfides; D016877:Oxidants; D047428:Protein Kinase Inhibitors; C466499:glutathione disulfide S-oxide; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019803:Glutathione Disulfide