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)

The effects of cerebral ischemia on calcium/calmodulin-dependent kinase II (CaM kinase II) were investigated using the rat four-vessel occlusion model. In agreement with previous results using rat or gerbil models of cerebral ischemia or a rabbit model of spinal cord ischemia, this report demonstrates that transient forebrain ischemia leads to a reduction in CaM kinase II activity within 5 min of occlusion onset. Loss of activity from the cytosol fractions of homogenates from the neocortex, striatum, and hippocampus correlated with a decrease in the amount of CaM kinase alpha and beta isoforms detected by immunoblotting. In contrast, there was an apparent increase in the amount of CaM kinase alpha and beta in the particulate fractions. The decrease in the amount of CaM kinase isoforms from the cytosol but not the particulate fractions was confirmed by autophosphorylation of CaM kinase II after denaturation and renaturation in situ of the blotted proteins. These results indicate that ischemia causes a rapid inhibition of CaM kinase II activity and a change in the partitioning of the enzyme between the cytosol and particulate fractions. CaM kinase II is a multifunctional protein kinase, and the loss of activity may play a critical role in initiating the changes leading to ischemia-induced cell death. To identify a structural basis for the decrease in enzyme activity, tryptic peptide maps of CaM kinase II phosphorylated in vitro were compared. Phosphopeptide maps of CaM kinase alpha from particulate fractions of control and ischemic samples revealed not only reduced incorporation of phosphate into the protein but also the absence of a limited number of peptides in the ischemic samples. This suggested that certain sites are inaccessible, possibly due to a conformational change, a covalent modification of CaM kinase II, or steric hindrance by an associated molecule. Verifying one of these possibilities should help to elucidate the mechanism of ischemia-induced modulation of CaM kinase II.
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PMID:Effect of cerebral ischemia on calcium/calmodulin-dependent protein kinase II activity and phosphorylation. 771 3

The exposure of cultured rat hippocampal neurons to 500 microM glutamate for 20 min induced a 55% decrease in the total Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) activity. The Ca(2+)-independent activity and autophosphorylation of CaM kinase II decreased to the same extent as the changes observed in total CaM kinase II activity, and these decreases in activities were prevented by pretreatment with MK-801, an N-methyl-D-aspartate (NMDA)-type receptor antagonist, and the removal of extracellular calcium but not by antagonists against other types of glutamate receptors and protease inhibitors. Similarly, the decrease in the CaM kinase II activity was induced by a Ca2+ ionophore, ionomycin. Immunoblot analysis with the anti-CaM kinase II antibody revealed a significant decrease in the amount of the enzyme in the soluble fraction, in contrast with the inverse increase in the insoluble fraction; thus, the translocation was probably induced during treatment of the cells with glutamate. These results suggest that glutamate released during brain ischemia induces a loss of CaM kinase II activity in hippocampal neurons, by stimulation of the NMDA receptor, and that inactivation of the enzyme may possibly be involved in the cascade of the glutamate neurotoxicity following brain ischemia.
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PMID:Glutamate-induced loss of Ca2+/calmodulin-dependent protein kinase II activity in cultured rat hippocampal neurons. 772 97

The influence of brain ischemia on the subcellular distribution and activity of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) was studied in various cortical rat brain regions during and after cerebral ischemia. Total CaM kinase II immunoreactivity (IR) and calmodulin binding in the crude synaptosomal fraction of all regions studied increase but decrease in the microsomal and cytosolic fractions, indicative of a translocation of CaM kinase II to synaptosomes. The translocation of CaM kinase II to synaptic junctions occurs but not to synaptic vesicles. The translocation in neocortex and CA3/DG (dentate gyrus) is transient, whereas in the hippocampal CA1 region, it persists for at least 1 day of reperfusion. The Ca2+/calmodulin-dependent activity of CaM kinase II in the subsynaptosomal fractions of neocortex is persistently decreased by up to 85%, despite the increase in CaM kinase II IR. The decrease in activity is more pronounced than the decline in IR, suggesting that CaM kinase II is covalently modified in the postischemic phase. The persistent translocation of CaM kinase II in the vulnerable ischemic CA1 region indicates that a pathological process is sustained in the area after the reperfusion phase and this may be of significance for ischemic brain injury.
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PMID:Persistent translocation of Ca2+/calmodulin-dependent protein kinase II to synaptic junctions in the vulnerable hippocampal CA1 region following transient ischemia. 779 23

Both CA1 and dentate gyrus regions of the hippocampal slice exhibit an irreversible loss of synaptic transmission after exposure to in vitro ischemic conditions (buffer without oxygen and glucose). However, after shorter durations of ischemia (8-10 min) the CA1 region shows an irreversible loss of synaptic responses, whereas the dentate gyrus region completely recovers synaptic responses upon reoxygenation. To determine biochemical mechanisms underlying this differential susceptibility, we have examined changes in Ca2+/calmodulin-dependent protein kinase II (CaM-KII) and cyclic AMP-dependent protein kinase activities in homogenates from CA1 and dentate gyrus regions of the hippocampal slice after increasing durations of in vitro ischemia. Time-dependent changes in CaM-KII activities were correlated with changes in electrophysiological responses. CA1 homogenates from slices exposed to 1 min of ischemia showed significant increases in CaM-KII activity, whereas there was no significant change in kinase activity in dentate homogenates after 1 min of ischemia. However, after longer durations of ischemia (5, 10, and 20 min) we found a time-dependent reduction in CaM-KII activity in both CA1 and dentate gyrus regions, whereas no change was detected in cyclic AMP-dependent protein kinase activity. Irreversible depression of CaM-KII activity was seen at shorter durations of ischemia (10 min) in the CA1 region than in dentate region (20 min), which correlated with irreversible effects on synaptic responses. Immunoblot analysis showed that the decrease in CaM-KII activity was not due to degradation of CaM-KII protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activity of Ca2+/calmodulin-dependent protein kinase II following ischemia: a comparison between CA1 and dentate gyrus in a hippocampal slice model. 796 41

Calmodulin and ATP affinity and total binding capacity were characterized for CaM kinase II isolated from control and ischemic animals. Ischemic CaM kinase II exhibited equivalent apparent affinity and total binding for calmodulin when compared to control enzyme. However, ischemic CaM kinase II exhibited a significant decrease in apparent affinity for ATP in saturation experiments. ATP binding was characterized using the ATP photoaffinity analog [alpha-32P] Azido-ATP. A significant decrease in total binding and binding affinity for ATP was observed for the alpha (50 kDa) and beta (60 kDa) subunits. The observation that ischemia induced an alteration of ATP binding without affecting calmodulin binding is consistent with the hypothesis that ischemia directly affects the ATP binding of CaM kinase II which results in subsequent inhibition of the enzyme.
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PMID:Ischemic brain injury selectively alters ATP binding of calcium and calmodulin-dependent protein kinase II. 839 12

Reversible spinal cord ischemia in rabbits induced a rapid loss of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) activity measured as incorporation of phosphate into exogenous substrates. About 70% of the activity was lost from the cytosolic fraction of spinal cord homogenates after 15 min of ischemia preceding irreversible paraplegia, which takes 25 min in this model. The loss of enzyme activity correlated with a loss of in situ renaturable autophosphorylation activity and a loss of CaM kinase II alpha and beta subunits in the cytosol detected by immunoblotting. CaM kinase II activity in the particulate fraction also decreased but the protein levels of the alpha and beta subunits increased. Thus ischemia resulted in an inactivation of CaM kinase II and a sequential or concurrent subcellular redistribution of the enzyme. However, denaturation and renaturation in situ of the CaM kinase subunits immobilized on membranes partly reversed the apparent inactivation of the enzyme in the particulate fraction. CaM kinase II activity was restored after reperfusion following short (< or = 25 min) durations of ischemia but not after longer durations (60 min) that result in irreversible paraplegia. The ischemia-induced inactivation of CaM kinase II, which phosphorylates proteins regulating many cellular processes, may be important in the cascade of events leading to delayed neuronal cell death.
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PMID:Inactivation and subcellular redistribution of Ca2+/calmodulin-dependent protein kinase II following spinal cord ischemia. 839 89

The microtubule-associated protein tau plays an important role in the dynamics of microtubule assembly necessary for axonal growth and neurite plasticity. Ischemia disrupts the neuronal cytoskeleton both by promoting proteolysis of its components and by affecting kinase and phosphatase activities that alter its assembly. In this study the effect of ischemia and reperfusion on the expression and phosphorylation of tau was examined in a reversible model of spinal cord ischemia in rabbits. tau was found to be dephosphorylated in response to ischemia with a time course that closely matched the production of permanent paraplegia. Dephosphorylation of tau was limited to the caudal lumbar spinal cord. In a similar manner, Ca2+/calmodulin-dependent kinase II activity was reduced only in the ischemic region. Thus, dephosphorylation of tau is an early marker of ischemia as is the rapid loss of Ca2+/calmodulin-dependent kinase II activity. tau, however, was rephosphorylated rapidly during reperfusion at site(s) that cause a reduction in its electrophoretic mobility regardless of the neurological outcome. Alterations in phosphorylation or degradation of tau may affect microtubule stability, possibly contributing to disruption of axonal transport but also facilitating neurite plasticity in a regenerative response.
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PMID:Changes in phosphorylation of tau during ischemia and reperfusion in the rabbit spinal cord. 852 66

The change in the subcellular distribution of Ca2+/calmodulin-dependent protein kinase II was studied in the rat hippocampus following normothermic and hypothermic transient cerebral ischemia of 15 min duration. A decrease in immunostaining of Ca2+/calmodulin-dependent protein kinase II was observed at 1 h of reperfusion which persisted until cell death in the CA1 region. In the CA3 and dentate gyrus areas immunostaining recovered at one to three days of reperfusion. The CA2+/calmodulin-dependent protein kinase II was translocated to synaptic junctions during ischemia and reperfusion which could be due to a persistent change in the intracellular calcium ion homeostasis. The expression of the messenger RNA of the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II decreased in the entire hippocampus during reperfusion, and was most marked in the dentate gyrus at 12 h of reperfusion. This decrease could be a feedback downregulation of the mRNA due to increased Ca2+/calmodulin-dependent protein kinase II activation. Intraischemic hypothermia protected against ischemic neuronal damage and attenuated the ischemia-induced decrease of Ca2+/calmodulin-dependent protein kinase II immunostaining in all hippocampal regions. Hypothermia also reduced the translocation of Ca2+/calmodulin-dependent protein kinase II and restored Ca2+/calmodulin-dependent protein kinase II alpha messenger RNA after ischemia. The data suggest that ischemia leads to an aberrant Ca2+/calmodulin-dependent protein kinase II mediated signal transduction in the CA1 region, which is important for the development of delayed neuronal damage. Hypothermia enhances the restoration of the Ca2+/calmodulin-dependent protein kinase II mediated cell signalling.
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PMID:Alterations of Ca2+/calmodulin-dependent protein kinase II and its messenger RNA in the rat hippocampus following normo- and hypothermic ischemia. 854 77

The activity of Ca2+/calmodulin-dependent protein kinase II (CaM-KII) during short-term global ischaemia was investigated in the gerbil brain hippocampus and cortex. Ischaemia of 0.5 min duration significantly stimulated Ca(2+)-independent 'autonomous' activity, indicating activation of the first step of intramolecular enzyme phosphorylation just after ischaemia has developed. Prolongation of the ischaemic period up to 5 min inhibited both Ca(2+)-dependent and, to a lesser extent, Ca(2+)-independent activities of CaM-KII. These last events coincide with an extensive translocation of CaM-KII protein from the soluble to the membranous fraction. In effect, in spite of inhibition of total CaM-KII activity, its Ca(2+)-independent, persistently active component can still remain more abundant at specific membrane regions.
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PMID:Brain ischaemia transiently activates Ca2+/calmodulin-independent protein kinase II. 873 Aug 47

The protein serine/threonine kinases which are highly expressed in the central nervous system (CNS) are severely affected by brain ischemia. Irrespective of substantial differences among the particular members of this group of kinases, their responses to ischemic stress show a lot of similarities. Initially they are switched on by facilitated interaction with their specific activators/second messengers like cyclic AMP, 1,2-sn-diacylglicerol and particularly Ca2+, then they are translocated to highly specific regions of plasma membranes. After phosphorylation of target proteins, the kinases are deactivated by means of different routes. Activity of PKA is regulated by its direct access to cAMP. In the case of CaMKII, it is probably achieved by its extensive, inhibitory autophosphorylations, while PKC seems to be proteolytically degraded. These biphasic changes in serine/threonine kinases activity may play a critical role in the evolution of postischemic brain injury and provide a mechanism for a variety of short- and long-term signalling events.
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PMID:Protein serine/threonine kinases (PKA, PKC and CaMKII) involved in ischemic brain pathology. 876 9


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