Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify the involvement of intracellular signaling pathway and calpain in the brain injury and its protection by mild hypothermia, immunoblotting analyses were performed in the rat brain after global forebrain ischemia and reperfusion. After 30 min of ischemia followed by 60 min of reperfusion, Ca2+/calmodulin-dependent kinase II (CaM kinase II) and protein kinase C (PKC)-alpha, beta, gamma isoforms translocated to the synaptosomal fraction, while mild hypothermia (32 degrees C) inhibited the translocation. The hypothermia also inhibited fodrin proteolysis caused by ischemia-reperfusion, indicating the inhibition of calpain. These effects of hypothermia may explain the mechanism of the protection against brain ischemia-reperfusion injury through modulating synaptosomal function.
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PMID:Hypothermia inhibits translocation of CaM kinase II and PKC-alpha, beta, gamma isoforms and fodrin proteolysis in rat brain synaptosome during ischemia-reperfusion. 1189 78

Excessive release of glutamate during transient cerebral ischemia initiates a cascade of events that leads to the delayed and selective death of neurons located in the hippocampus. Activity of calcium calmodulin kinase II (CaM kinase), a protein kinase critical to neuronal functioning, disappears following ischemia. The in vivo link between glutamate excitoxicity and alterations in CaM kinase activity has not been extensively studied. Baclofen, a selective gamma-aminobutyric acid (GABA)(B) receptor agonist, has been shown to inhibit glutamate release. The present study evaluated the neuroprotective efficacy of this compound and assessed early changes in hippocampal-dependent behaviors and CaM kinase immunoreactivity following transient cerebral ischemia. Baclofen (50 mg/kg) prevented both the loss of hippocampal CA1 pyramidal cells and the reduction in hippocampal CaM kinase immunoreactivity observed in control animals following ischemic insult. Cerebral ischemia produced a significant increase in working memory errors; however, baclofen failed to attenuate this memory deficit. Results confirm that baclofen is neuroprotective and support a link between glutamate excitotoxicity and reductions in CaM kinase immunoreactivity.
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PMID:Baclofen is neuroprotective and prevents loss of calcium/calmodulin-dependent protein kinase II immunoreactivity in the ischemic gerbil hippocampus. 1189 95

During and after middle cerebral artery occlusion in mice, CaMKII alpha protein was irreversibly translocated from the soluble to the Triton X-100-nonsoluble fraction. This decrease in solubility had a strong effect on activity: CaMKII alpha was almost completely inactivated after being translocated. Results from solubilization experiments suggest that different mechanisms underlie the conversion of CaMKII alpha protein from a soluble to a detergent nonsoluble form in ischemic as opposite to nonischemic tissue. Analysis of the phosphorylation state of CaMKII alpha revealed that in the total homogenate and the Triton X-100-nonsoluble fraction, CaMKII alpha phosphorylated at only one site was the dominant phosphorylated form, whereas in the soluble fraction CaMKII phosphorylated at two sites was the predominant phosphorylated species. Investigation of the mechanisms underlying ischemia-induced changes in the solubility of CaMKII alpha could help to elucidate processes triggered by transient focal cerebral ischemia that lead to neuronal cell injury.
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PMID:Phosphorylation state, solubility, and activity of calcium/calmodulin-dependent protein kinase II alpha in transient focal ischemia in mouse brain. 1219 52

Ca(2+)/calmodulin-dependent protein kinase (CaMK) family is responsive to changes in the intracellular Ca(2+) concentration. However, their functions have not been well established in the ischemia/reperfusion heart. The effects of myocardial ischemia on CaMKII, the most strongly expressed form, were investigated using isolated rat hearts. Rat hearts were rendered globally ischemic by stopping perfusion for 15 min, and then reperfused, heart ventricles being analyzed in each phase. Western blotting detected a decrease in the cytosolic and concomitant increase in the particulate fraction of CaMKII following transient ischemia. Redistribution to the cytosol was revealed on reperfusion. Northern blot showed CaMKII gene expression decreased by ischemia. Furthermore, autoradiography and confocal immunohistochemical findings provided autophosphorylation of CaMKII in the cytosol, ischemia causing decrease, with gradual recovery on reperfusion. These results indicate a transient partial translocation of CaMKII accompanied by kinase activity, with residual myocardial CaMKII undergoing autophosphorylation during ischemia and reperfusion, demonstrating two different characteristic dynamics of CaMKII.
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PMID:Dynamics of Ca(2+)/calmodulin-dependent protein kinase II following acute myocardial ischemia-translocation and autophosphorylation. 1235 53

In this article, we investigated the autophosphorylation and translocation of calcium/calmodulin-dependent protein kinase II alpha (CaMKII alpha) in hippocampus during global ischemia. The following results were observed: (1) CaMKII alpha immediately became autophosphorylated after 3 min ischemia, at the same time, there is a dramatic and sustained translocation of CaMKII alpha from cytosolic fraction to synaptic fraction; (2) CaMKII alpha translocated to post-synaptic density and targeted N-methyl-D-aspartate receptor subunit 2B (NR2B) which was serine-phosphorylated by active CaMKII alpha; (3) serine phosphorylation of NR2B could not only inhibit the formation of CaMKII alpha-NR2B complexes but also promote the dissociation of the preformed complexes when ischemic time was prolonged. These results suggest that phosphorylation of NR2B can influence the channel properties of NR2B, and the dissociation of the CaMKII alpha-NR2B complexes may be a negative feedback mechanism during longer time cerebral ischemia.
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PMID:Autophosphorylated calcium/calmodulin-dependent protein kinase II alpha induced by cerebral ischemia immediately targets and phosphorylates N-methyl-D-aspartate receptor subunit 2B (NR2B) in hippocampus of rats. 1240 60

It has been reported that cerebral ischemia induces Thr286 autophosphorylation and translocation of CaMKIIalpha which targets to and phosphorylates NR2B in hippocampus of rats [Neuroscience 96 (2000) 665; J. Biol. Chem. 275 (2000) 23798]. To further illustrate the mechanisms underlying these processes, we examined the effects of ketamine (a selective antagonist of NMDA receptor), KN-62 (1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine, a selective inhibitor of CaMKII) and reperfusion on CaMKII and NMDA receptors and the interactions between these signal proteins. Firstly, our results showed that ketamine decreased the ischemia-induced autophosphorylation, translocation and the targeting of CaMKIIalpha to NR2B and the serine-phosphorylation of NR2B. Secondly, KN-62 also inhibited the autophosphorylation of CaMKIIalpha, NR2B serine-phosphorylation and the binding of CaMKIIalpha to NR2B but had no effect on the translocation of CaMKII. These data strongly suggest that NMDA receptor channels mediated the Ca(2+)-dependent activation of CaMKII and NMDA receptors surely were the substrates on membranes of active CaMKII. Thirdly, our results indicated the concomitant phosphorylation and dephosphorylation of CaMKII and NR2B following ischemia or longer reperfusion. Moreover, the dissociation of CaMKII from NR2B had the same trend as that of the return of CaMKII to cytosol. All these data imply the close relationships between CaMKII and NR2B during ischemia and reperfusion, namely, CaMKII might act as an amplifier of detrimental cellular calcium signal regulated by NMDA receptors when becoming autophosphorylated and targeting to NR2B; conversely, autophosphorylated CaMKII could modulate NMDA receptor channel properties by phosphorylating NR2B.
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PMID:Autophosphorylated calcium/calmodulin-dependent protein kinase II alpha (CaMKII alpha) reversibly targets to and phosphorylates N-methyl-D-aspartate receptor subunit 2B (NR2B) in cerebral ischemia and reperfusion in hippocampus of rats. 1265 Sep 77

Phosphorylation of the GluR1 subunit of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor has been implicated in the regulation of the receptor channel. We investigated the effects of transient global ischemia in rats on phosphorylation of the GluR1 subunit in the hippocampal CA1 and CA3/dentate gyrus. Transient ischemia induced an increase in the phosphorylation of GluR1 at Ser831 in the CA1 at 1 h of reperfusion. In contrast, the phosphorylation of Ser845 in neither region was affected by the ischemia. The amounts of calcium/calmodulin-dependent kinase (CaMKII) and its activated form, but not cAMP-dependent protein kinase subunits, were increased in a crude membrane fraction after ischemia. The results suggest that an activated CaMKII may phosphorylate Ser831 of GluR1 and a consequent phosphorylation of GluR1 may be related to pathogenic events occurring in the vulnerable subfield of the hippocampus after transient global ischemia.
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PMID:Transient global ischemia enhances phosphorylation of the GluR1 subunit of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor in the hippocampal CA1 region in rats. 1267 37

The status of phospholamban (PLB) phosphorylation in the ischemia-reperfused hearts remains controversial. Although a decrease in the phosphorylation of both PLB residues (Ser16, PKA site, and Thr17, CaMKII site) was previously reported, experiments from our laboratory failed to detect this decrease. In an attempt to elucidate the cause for this discrepancy, experiments were performed in Langendorff-perfused rat hearts with two main goals: (1) To determine whether keeping pacing during ischemia, a protocol followed in other ischemia-reperfusion models, decreases the phosphorylation of PLB residues, below pre-ischemic values; (2) To investigate whether a maximal beta-adrenergic challenge allows to detect a decrease in the ability of PLB to be phosphorylated in ischemia-reperfused hearts. Hearts were submitted to a global ischemia/reperfusion protocol (20/30 min) with (P) or without (NP) pacing during ischemia, and phosphorylation of PLB residues was assessed by immunodetection. The recovery of contractility upon reperfusion was lower in P vs. NP hearts. Ser16 of PLB, was phosphorylated at the end of ischemia in NP hearts. This increase appeared earlier in P hearts and was significantly diminished by catecholamine depletion and beta-blockade. Thr17 site was phosphorylated at the beginning of ischemia and the onset of reperfusion. The ischemia-induced phosphorylation of Thr17 was higher and more sustained in P vs. NP hearts, and inhibited by the calcium channel blocker, nifedipine, whereas the reperfusion-induced increase in Thr17 phosphorylation was similar in P and NP hearts and was significantly diminished by the Na+/Ca2+ exchanger inhibitor KB-R7943. Phosphorylation of PLB residues did not decrease below basal levels at any time during ischemia and reperfusion. However, the phosphorylation, inotropic and lusitropic response to beta-adrenergic stimulation was significantly decreased both in P and NP hearts.
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PMID:Phospholamban phosphorylation in ischemia-reperfused heart. Effect of pacing during ischemia and response to a beta-adrenergic challenge. 1457 98

Hyperglycemia and hypercapnia aggravate intra-ischemic acidosis and subsequent brain damage. However, hyperglycemia causes more extensive post-ischemic damage than hypercapnia, particularly in the cingulate cortex. We investigated the changes in the subcellular distribution of protein kinase Cgamma (PKCgamma) and the Ca2+/calmodulin-dependent protein kinase II (CaMKII), as well as changes in protein tyrosine phosphorylation during and following 10 min normoglycemic, hyperglycemic (plasma glucose approximately 20 mM) and hypercapnic (paCO2) approximately 300 mm Hg) global cerebral ischemia. During reperfusion period, the translocation to cell membranes of PKCgamma, but not CaMKII, was prolonged by intra-ischemic hyperglycemia, while it was only marginally affected by hypercapnia. The tyrosine-phosphorylation of proteins in the synaptosomal membranes, as well as the extracellular signal-regulated kinase (ERK) in the cytosol, markedly increased during reperfusion following hyperglycemic ischemia, but to a lesser degree following hypercapnic ischemia. Our data suggest that PKCgamma, tyrosine kinase and ERK systems are involved in the process of ischemic damage in the cingulate cortex, where hyperglycemia may affect these kinases through an additional mechanism other than exaggerated acidosis.
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PMID:Hyperglycemia and hypercapnia differently affect post-ischemic changes in protein kinases and protein phosphorylation in the rat cingulate cortex. 1467 11

The levels of protein kinase C-gamma (PKC-gamma ) and the calcium/calmodulin-dependent kinase II-alpha (CaMKII-alpha) were measured in crude synaptosomal (P2), particulate (P3), and cytosolic (S3) fractions of the neocortex of rats exposed to 1-hour and 2-hour middle cerebral artery occlusion (MCAO) and 2-hour MCAO followed by 2-hour reperfusion. During MCAO, PKC levels increased in P2 and P3 in the most severe ischemic areas concomitantly with a decrease in S3. In the penumbra, PKCgamma decreased in S3 without any significant increases in P2 and P3. Total PKC-gamma also decreased in the penumbra but not in the ischemic core, suggesting that the protein is degraded by an energy-dependent mechanism, possibly by the 26S proteasome. The CaMKII-alpha levels increased in P2 but not P3 during ischemia and reperfusion in all ischemic regions, particularly in the ischemic core. Concomitantly, the levels in S3 decreased by 20% to 40% in the penumbra and by approximately 80% in the ischemic core. There were no changes in the total levels of CaMKII-alpha during MCAO. The authors conclude that during and after ischemia, PKC and CaMKII-alpha are translocated to the cell membranes, particularly synaptic membranes, where they may modulate cellular function, such as neurotransmission, and also affect cell survival. Drugs preventing PKC and/or CaMKII-alpha translocation may prove beneficial against ischemic cell death.
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PMID:Protein kinase C-gamma and calcium/calmodulin-dependent protein kinase II-alpha are persistently translocated to cell membranes of the rat brain during and after middle cerebral artery occlusion. 1468 16


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