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. 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. Ca2+/calmodulin (CaM) 2The abbreviations used are:CaMcalmodulinCaMKIICa2+/CaM-dependent protein kinase IINMDAN-methyl-d-aspartic acidGS-DSOglutathione disulfide S-oxideGS-DSMOglutathione disulfide S-monoxideGS-DSDOglutathione disulfide S-dioxideSNPsodium nitroprussidePMSFphenylmethanesulfonyl fluorideDTTdithiothreitolPSDpost synaptic densityHFShigh frequency stimulationEPSPexcitatory postsynaptic potentialfEPSPfield EPSPACSFartificial cerebrospinal fluidLTPlong term potentiation.2The abbreviations used are:CaMcalmodulinCaMKIICa2+/CaM-dependent protein kinase IINMDAN-methyl-d-aspartic acidGS-DSOglutathione disulfide S-oxideGS-DSMOglutathione disulfide S-monoxideGS-DSDOglutathione disulfide S-dioxideSNPsodium nitroprussidePMSFphenylmethanesulfonyl fluorideDTTdithiothreitolPSDpost synaptic densityHFShigh frequency stimulationEPSPexcitatory postsynaptic potentialfEPSPfield EPSPACSFartificial cerebrospinal fluidLTPlong term potentiation.-dependent protein kinase II (CaMKII) is one of the major Ca2+-sensing enzymes important in transducing neuronal, hormonal, and electrical signals in brain, heart, and other tissues. In the central nervous system, CaMKII plays a pivotal role in the facilitation of synaptic plasticity, learning, and memory and in activity-dependent developmental processes (1Lisman J. Schulman H. Cline H. Nat. Rev. Neurosci. 2002; 3: 175-190Crossref PubMed Scopus (1446) Google Scholar). CaMKII holoenzyme is a dodecamer composed of two stacked hexameric rings, in which each catalytic/regulatory domain from the upper ring interacts with the equivalent catalytic/regulatory domain in the lower ring by an antiparallel coiled-coil, which resides in regulatory domains (2Rosenberg O.S. Deindl S. Sung R.J. Nairn A.C. Kuriyan J. Cell. 2005; 123: 849-860Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). Binding of Ca2+/CaM to the regulatory domain separates the dimer pair and causes the exposure of Thr-286 or Thr-287 (within α or β subunit) for phosphorylation by another catalytic domain in the same ring. This inter-subunit phosphorylation of Thr-286/287 converts the kinase into a high affinity binding protein for Ca2+/CaM, and the kinase becomes an activator-independent autonomous enzyme (3Rich R.C. Schulman H. J. Biol. Chem. 1998; 273: 28424-28429Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). The autophosphorylation also leads to increased affinity of the kinase for several proteins near the sites of elevated Ca2+ with functional consequences (4Merrill M.A. Chen Y. Strack S. Hell J.W. Trends Pharmacol. Sci. 2005; 26: 645-653Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 5Leonard A.S. Bayer K.U. Merrill M.A. Lim I.A. Shea M.A. Schulman H. Hell J.W. J. Biol. Chem. 2002; 277: 48441-48448Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). calmodulin Ca2+/CaM-dependent protein kinase II N-methyl-d-aspartic acid glutathione disulfide S-oxide glutathione disulfide S-monoxide glutathione disulfide S-dioxide sodium nitroprusside phenylmethanesulfonyl fluoride dithiothreitol post synaptic density high frequency stimulation excitatory postsynaptic potential field EPSP artificial cerebrospinal fluid long term potentiation. calmodulin Ca2+/CaM-dependent protein kinase II N-methyl-d-aspartic acid glutathione disulfide S-oxide glutathione disulfide S-monoxide glutathione disulfide S-dioxide sodium nitroprusside phenylmethanesulfonyl fluoride dithiothreitol post synaptic density high frequency stimulation excitatory postsynaptic potential field EPSP artificial cerebrospinal fluid long term potentiation. In the brain, translocation and clustering of CaMKII have been implicated in the NMDA receptor-dependent enhancement of synaptic plasticity (6Otmakhov N. Tao-Cheng J.H. Carpenter S. Asrican B. Dosemeci A. Reese T.S. Lisman J. J. Neurosci. 2004; 24: 9324-9331Crossref PubMed Scopus (207) Google Scholar, 7Tao-Cheng J.H. Vinade L. Winters C.A. Reese T.S. Dosemeci A. Neuroscience. 2005; 130: 651-656Crossref PubMed Scopus (11) Google Scholar, 8Shen K. Meyer T. Science. 1999; 284: 162-166Crossref PubMed Scopus (534) Google Scholar, 9Shen K. Teruel M.N. Connor J.H. Shenolikar S. Meyer T. Nat. Neurosci. 2000; 3: 881-886Crossref PubMed Scopus (176) Google Scholar) as well as in neurological disorders associated with ischemic injury (10Hu B.R. Park M. Martone M.E. Fischer W.H. Ellisman M.H. Zivin J.A. J. Neurosci. 1998; 18: 625-633Crossref PubMed Google Scholar, 11Aronowski J. Grotta J.C. Waxham M.N. J. Neurochem. 1992; 58: 1743-1753Crossref PubMed Google Scholar, 12Dosemeci A. Reese T.S. 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PubMed Scopus Google Scholar). we showed that of NMDA or of oxidants to the brain of and formation of disulfide of this protein J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Neurochem. PubMed Scopus Google Scholar). The of protein was as a of oxidation by the glutathione disulfide S-oxides which have a high to disulfide and disulfide of proteins Pharmacol. 2002; PubMed Scopus Google Scholar, J. 2000; PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of CaMKII by and with other proteins been of this enzyme by not been In this we showed that CaMKII in mouse brain and in the purified is very susceptible to Interestingly, a oxidative of CaMKII was observed in the acutely prepared mouse hippocampal ischemic Using two potential mediators of oxidants in the brain, glutathione disulfide S-monoxide (GS-DSMO) and glutathione disulfide S-dioxide (GS-DSDO), we that the purified CaMKII oxidized by these two those enzymes in the oxidant-treated synaptosomes and in the ischemic hippocampal slices. The ischemia-evoked oxidation of CaMKII was not reversed by and this oxidative also the autophosphorylation of the kinase and synaptic potentiation post ischemia. of was by the of and The used in the were from the sodium nitroprusside diamide, glutathione glutathione and phenylmethanesulfonyl fluoride from from from and from a from protein and from from from mouse protein from mouse α and β CaMKII from and mouse α CaMKII from of and Treatment with were a with 10 of and to J.W. J.A. PubMed Scopus Google Scholar). The was at for 10 and of the to were of each each of and in in at for the at of and were with and and at for The was with and in and at for synaptosomes were with H2O2, diamide, and for of CaMKII, were at for at and the was in were prepared by of the in sodium sodium and each of and and at for to the for (10 was to the oxidant-treated and to the were prepared by of the in 10 were by and for in with and without to and with the of from was prepared by a from the previously J. Biol. PubMed Scopus Google Scholar, J. Neurosci. PubMed Scopus Google Scholar). prepared synaptosomes were with or for 10 in The was with (10 and in at for at The were in of and and at for The was at for and the were in of the same The were of and of and at for at a The were in of of and at for a The was by in of and of were by of and of hippocampal were prepared from as previously J. J. Neurosci. 26: PubMed Scopus Google Scholar) and were in at for for recovery after ischemic were in a 10 previously with the hippocampal of ischemia J. J. Waxham M.N. J. Neurochem. PubMed Google Scholar). were from the and in of 10 were at for at and the was in of the same of proteins from the and were by and to and with CaMKII of the kinase were after of the were in and the were for CaMKII with or without Ca2+/CaM with as a were in a with for stimulation of and for of field EPSP from the of the were with at a of and a was at with a that of the a with were to ischemia by with with for 10 and to of for at 10 the were to high frequency stimulation at for The control were with and stimulated with the same were by and by The of the was used to the after was as of the of after the of were and of mouse brain, after of and brain was with in 10 of and and the was at at for The was in the same of the and to the The was with at for and the protein in and The was by and through a a and with each of and CaMKII was from the with and kinase were and by The purified enzyme was at and was by CaMKII was at for in a and Treatment of CaMKII with was in 10 and at for to protein These proteins were which been with the same and at for in an to reduced kinase from and were of oxidants to the which were the after of the in the CaMKII was with at for the and the was by of 10 were by or and to for of CaMKII, were at the and the was with as a the effects of oxidation CaMKII the enzyme was with oxidants at for 10 and of with CaMKII autophosphorylation was for in a and was by the of with or without and by with α density of CaMKII was to the of and J. Biol. Chem. Full Text PDF PubMed Google Scholar) with an CaMKII or protein and were of a in and at at for in a with the and at of were from the and other was for CaMKII by or The of proteins was identified by the with and of and were as previously PubMed Scopus Google Scholar). was by proteins in by to was by and was by or by were by the were as and were of or In was of CaMKII in the oxidative of CaMKII, we mouse brain for the in CaMKII is to be in the synaptosomes and treatment of these with and caused an of the CaMKII as compared with the control The activator-independent with the of the one was not significantly by these that these oxidants the The from with and with control were by and with α or β CaMKII that these oxidants caused oxidation of the kinase to aggregates These aggregates were by disulfide as by of these high The of the α and β were reduced or and their were the The of the kinase and the α CaMKII was also susceptible to oxidative the autophosphorylated α CaMKII was reduced as compared with the the activator-independent remained with the of that with the oxidized α CaMKII as These that oxidative of CaMKII through formation of disulfide of the CaMKII with the been to associate with the interacts with several postsynaptic and of the which a may the with binding oxidants caused in the of CaMKII with the oxidant-treated synaptosomes were in to the and by density to these were by with α and The of oxidized CaMKII in the those in The protein in the of the oxidant-treated increased by the the control relatively CaMKII aggregates in the these aggregates in the that the oxidized CaMKII is associated with and the enzyme in the In the oxidized a of CaMKII was associated with the the CaMKII in a pair of in the of the the were in the for These that oxidants a of α CaMKII other disulfide and may as a for oxidative of the control also this in the is that oxidation of CaMKII also in of CaMKII by CaMKII by the oxidant-treated synaptosomes was a of those purified mouse CaMKII was with H2O2, diamide, and for and at and caused a level of disulfide formation which was by a in the Ca2+/CaM-dependent kinase at the without the The in the purified enzyme was of the activity. Oxidation of CaMKII with at and caused a formation of disulfide with in the kinase a in the activator-independent at In at and disulfide also caused an in the kinase at the oxidant-treated CaMKII was the disulfide were reduced without of to and the kinase α CaMKII as the control These that the oxidative of CaMKII by these oxidants not those in the synaptosomes. we showed that treatment of brain with oxidants oxidized glutathione and which caused protein and formation of protein disulfide J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the purified CaMKII with at and and at and caused of the kinase by was at α CaMKII to aggregates a relatively level of caused of α and β CaMKII in an in the as by a and formation of to of α and were relatively in β CaMKII to aggregates these oxidized were with the of the to the kinase were as α and β not The of of the purified CaMKII by and after was to of the kinase showed that oxidation of CaMKII by caused a in to was a of the kinase The level of inhibition of CaMKII by be by with 10 the other the GS-DSDO-mediated inhibition of CaMKII be by with 10 that an is for the of the kinase activity. These also caused effects the autophosphorylation of CaMKII, by with α CaMKII, as those the phosphorylation of not of the of of the oxidized CaMKII by of the of disulfide formation without of the of the of aggregation and the oxidized CaMKII was to density and by and with α The purified kinase in the of is a to which density this the kinase did not inter-subunit disulfide caused a of the enzyme to of as by the of the throughout the that were the of the kinase that increased the of clustering to which to the of the of Ca2+/CaM in the of increased the aggregation A. Waxham M.N. J. Neurochem. PubMed Scopus Google Scholar) showed that CaMKII in the of Ca2+/CaM (10 and at as a of that of CaMKII at was also in by disulfide the of CaMKII by caused a high of clustering that in the formation of which at the of the density of Ca2+/CaM the clustering In was in CaMKII the of the which in an in the of the The CaMKII did not to be significantly in the of Ca2+/CaM These that these disulfide of CaMKII of the mouse CaMKII very and autophosphorylation the increased to of the activity. of the autophosphorylated kinase with caused a in the and with caused a inhibition of the and In to the CaMKII, oxidation of the autophosphorylated CaMKII by did not high which to the of the density the of the inter-subunit were reduced to a and of to α remained in this autophosphorylated kinase with α CaMKII that the autophosphorylated α CaMKII was not to aggregates as was the enzyme Oxidation of the autophosphorylated CaMKII with caused and formation of aggregates the aggregates were two of of and with α CaMKII that the autophosphorylated CaMKII did not aggregates Oxidation of CaMKII in the that oxidative of CaMKII we the of ischemia the enzyme in the acutely prepared mouse hippocampal slices. exposure of the in with for the were in 10 and by into and were by for α CaMKII and The and α CaMKII and the was reduced the of these two in the and and and the of exposure to ischemic In in the the oxidized two of a control from after 10 and of ischemia the in the oxidized was not the the of the oxidized was reduced the to of these increased by at to at min) and The in these in the hippocampal ischemia those of the oxidant-treated synaptosomes of the ischemic with protein to of CaMKII not and was of α CaMKII and These that oxidative of α CaMKII not and the formation of and aggregates may of and of the synaptic response of the hippocampal CA1 region showed that ischemia caused a depression of the basal response that near 10 and re-oxygenation the response in 10 Oxidation of CaMKII by the of to near at and was at elevated throughout the re-oxygenation for and after of ischemia or for 10 and after 10 of ischemia in the level of CaMKII oxidation significantly elevated that of the pre-ischemic Oxidation of CaMKII in a near of CaMKII by the autonomous kinase with of ischemia the autonomous kinase was of the and after 10 was However, the oxidative autonomous kinase did to of the control after of re-oxygenation. with α CaMKII that ischemia caused CaMKII and re-oxygenation autophosphorylation the ischemia (10 to the was to the hippocampal to the of the stimulation after control and of after control were significantly lower in the compared with the control The ischemia-evoked oxidation of CaMKII that in the of the and autonomous kinase the CaMKII is one of the proteins in the brain, and as a protein kinase as well as an for with several and of the of this kinase is to aggregates in neuronal and a of (6Otmakhov N. 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Full Text Full Text PDF PubMed Scopus Google aggregates In the acutely prepared hippocampal slices, the α CaMKII for in the and in the of the enzyme in the This high of the α CaMKII in the control that several in this enzyme very susceptible to that of oxidants is to CaMKII to ischemic the of oxidation was Thus, the of CaMKII aggregation be by in as well as in the Treatment of synaptosomes with H2O2, diamide, and caused CaMKII to and aggregates and these not be by the same treatment of the purified enzyme with these In oxidation of purified CaMKII with those aggregates in the oxidant-treated synaptosomes and in the hippocampal to ischemic stress These that or their the These not CaMKII to in they also CaMKII and other of CaMKII and proteins associated with the may a critical role in and signal of the to that they were from the of the to be the formation of these to α CaMKII may as of oxidation of this enzyme in at potential oxidative of CaMKII, and formation of and CaMKII Treatment of purified CaMKII with at caused aggregates with inhibition of the kinase an that formation of inter-subunit disulfide is not a Treatment of CaMKII with caused aggregation and of CaMKII, and the level of inhibition be by that these the other of CaMKII with caused and formation of oxidized that in a of inhibition that by The inhibition be by that formation of oxidized is for the of In the oxidant-treated synaptosomes or hippocampal to was by protein or by Thus, that the in the kinase in the synaptosomes and hippocampal from formation of the to This which the of CaMKII to is a of the is also that of NMDA from and disulfide formation J. Neurosci. PubMed Scopus Google Scholar, H. Y. T. Y. H. Chen Full Text Full Text PDF PubMed Scopus Google Scholar) may also to the response in of hippocampal to the ischemic the of and CaMKII oxidized and and the kinase was the oxidized kinase and the CaMKII remained at the pre-ischemic autophosphorylation of CaMKII in these processes that causes a in protein phosphorylation and from in the of The in the basal synaptic which is a of the caused by the in activity. Thus, oxidation of CaMKII and the of CaMKII and autophosphorylation may not a role in the basal synaptic of CaMKII at Thr-286 the domain the catalytic domain autonomous and Ca2+/CaM The of the catalytic domain may the formation of Thus, oxidative of the autophosphorylated CaMKII by caused a of aggregation. The reduced of the autophosphorylated CaMKII to aggregates is to that of the autophosphorylation in the A. H. A. Schulman H. Waxham M.N. J. 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