Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoradiographic localizations of major second messengers and a selective cyclic adenosine monophosphate (cyclic-AMP) phosphodiesterase in the brain were visualized in the gerbil and the rat using receptor autoradiography. [3H]Phorbol 12,13-dibutyrate (PDBu), [3H]inositol 1,4,5-trisphosphate (IP3), [3H]forskolin, [3H]cyclic-AMP, and [3H]rolipram were used to label protein kinase C, IP3 receptor, adenylate cyclase, cyclic-AMP-dependent protein kinase (cyclic-AMP-DPK), and Ca2+/calmodulin-independent cyclic-AMP phosphodiesterase (PDE), respectively. Most second messengers and rolipram binding activities were especially found in the limbic system, basal ganglia, and cerebellum. Marked differences were noted in the hippocampus, where cyclic-AMP and rolipram binding activities were very low in gerbils but high in rats. In contrast, regional localization in the binding sites of PDBu, IP3, and forskolin in gerbil brain was relatively similar to that in rat brain. Further, alteration of the cyclic-AMP and rolipram binding sites was studied in the gerbil hippocampus 7 days after 10-min cerebral ischemia. The results suggest that the gerbil differs from the rat with respect to the characteristic neurons or interneurons, especially in the hippocampal formation. This finding may help further elucidate the relationship or difference between gerbils and rats for brain function and behavioral pharmacology. Furthermore, our results suggest that cyclic-AMP and rolipram binding sites are predominantly distributed on the pyramidal cell layer of the hippocampal CA1 sector and that transient cerebral ischemia can cause marked reduction in these binding sites in the hippocampus.
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PMID:Mapping of second messenger and rolipram receptors in mammalian brain. 132 28

The effect of transient cerebral ischemia on the expression of Ca2+/calmodulin dependent protein kinase II (CaM kinase II) mRNA in the gerbil brain was analyzed by Northern blots using cDNA clones for CaM kinase II. Ten minutes of bilateral carotid occlusion and 30 min of reperfusion resulted in reduced protein levels for alpha and beta subunits of the CaM kinase II, decreasing to 35% of control levels at 24 h. Recovery of immunoreactivity was detected in the cortex after 48 h. Eight to twelve hours after ischemia, the cortex showed a decrease in alpha and beta CaM kinase II mRNA levels. By 12-24 h of reperfusion the level of CaM kinase II mRNA was reduced to 26% of the control mRNA levels. CaM kinase II mRNA levels recovered by 48 h after ischemia, coinciding with the increase in CaM kinase II protein immunoreactivity. These results suggest that CaM kinase II is involved in neuronal survival through the reorganization of the neuroarchitecture and that the regulation of this role is controlled at the level of gene expression.
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PMID:Calcium/calmodulin dependent protein kinase II mRNA in the gerbil brain after cerebral ischemia. 133 17

Hypothermia was first applied therapeutically as a local anesthetic and later was used to achieve organ protection during procedures necessitating circulatory interruption. Profound whole-body hypothermia, typically carried out in conjunction with extracorporeal bypass, has long been employed during cardiac and neurosurgical operative procedures. More recently, studies in small-animal experimental models of cerebral ischemia have provided persuasive evidence that even small decreases in brain temperature confer striking protection against ischemic neuronal injury. By contrast, small elevations of brain temperature during ischemia accelerate and extend pathologic changes in the brain and promote early disruption of the blood-brain barrier. Hypothermia retards the rate of high-energy phosphate depletion during ischemia and promotes postischemic metabolic recovery. More importantly, mild intraischemic hypothermia markedly attenuates the release of glutamate into the brain's extracellular space and significantly diminishes the release of dopamine. Similarly, the inhibition of calcium-calmodulin-dependent protein kinase II triggered by normothermic ischemia is prevented by hypothermia, as is the ischemia-induced translocation and inhibition of the key regulatory enzyme protein kinase C. Hypothermia also appears to facilitate the resynthesis of ubiquitin following ischemia. Studies of potential clinical importance have shown that moderate hypothermia is capable of attenuating ischemic damage even if instituted early in the postischemic period. In the setting of focal cerebral ischemia, moderate brain hypothermia reduces the infarct size (particularly in the setting of reversible middle cerebral artery occlusion); conversely, hyperthermia markedly increases the infarct volume. These studies underscore the importance of monitoring and regulating the brain temperature during experimental studies of cerebral ischemia to insure a consistent pathologic outcome and to avoid the false attribution of "pharmacoprotection" to drugs that reduce the body temperature. The measurement of brain temperature is now practicable in neurosurgical patients requiring invasive monitoring, and human studies have shown that cortical and cerebroventricular temperatures may exceed systemic temperatures. Mild to moderate decreases in brain temperature are neuroprotective in cerebral ischemia, while mild elevations of brain temperature are markedly deleterious in the setting of ischemia or injury. It is anticipated that controlled clinical trials of therapeutic brain temperature modulation will be undertaken over the next several years.
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PMID:Therapeutic modulation of brain temperature: relevance to ischemic brain injury. 138 56

In this report we describe changes in the intracellular redistribution of raf serine/threonine protein kinase (product of the raf proto-oncogene family) in hippocampal neurons following cerebral ischemia in Mongolian gerbils. For immunohistochemical localization studies polyclonal antisera specific for each of the A, B, and Raf-1 isotypes of raf, as well as a pan-raf antisera, were employed. Of these, only sera recognizing B-raf, as well as the general v-raf (raised against the conserved C-terminal region) were positive, indicating that B-raf is the major isotype in this neuronal region. Three different ischemic models were used (repeated 3 times for two min and single 5 or 15 min occlusions, of the common carotid arteries) to demonstrate that ischemic insult causes redistribution of raf protein kinase into the cell nucleus of hippocampal neurons. Increased amounts of raf protein in the nuclei of pyramidal cells following ischemia was confirmed by Western blot analysis of isolated nuclear fractionations. Moreover, an elevation in the level of nuclear raf protein also was detected in the contralateral (i.e. non-occluded hemisphere) neurons of CA1 and CA3 subfields 4 days after the ischemic insult indicating a possible transsynaptic increase in the amount of raf protein along with redistribution. The intranuclear translocation of the immunoreactive material started from the perinucleolar rim and with time extended throughout the nucleus. Enhanced levels and altered redistribution of the raf polypeptide in the nuclei of pyramidal cells of the CA3 subfield appears to be reversible and returns to the normal level 12 days following the ischemic insult.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cerebral ischemia induces transient intracellular redistribution and intranuclear translocation of the raf proto-oncogene product in hippocampal pyramidal cells. 206 47

The possible activation of protein kinase C (PKC) during total cerebral ischemia was investigated in the rat. Translocation of PKC activity from the soluble to the particulate fraction was used as an index of PKC activation. There was a drop in the proportion of particulate PKC activity from 30% for controls to 20% by 30 min of ischemia (p less than 0.01). By 20 min of cardiac arrest, there was a 40% decline of the total cellular PKC activity (p less than 0.01). This was not accompanied by an increase in activator-independent activity, a finding indicating PKC was not being converted to protein kinase M. These data suggest that PKC was not activated during ischemia, but rather that ischemia causes a reduction in cellular PKC activity. Translocation of PKC activity to the particulate fraction was not observed in the cerebral cortex or hippocampus of reperfused brain for up to 6 h of recovery following 11-13 min of total cerebral ischemia. The level of total, soluble, and particulate PKC activity in the cerebral cortex was reduced (p less than 0.05), corresponding to the decrease observed by 15 min of ischemia without reflow. A similar decline in activity was also observed in the hippocampus. No increase in activator-independent activity was observed. These data suggest that PKC was inhibited during cerebral ischemia and that this reduced level of PKC activity was maintained throughout 6 h of recovery. We conclude that pathological activation of PKC was not responsible for the evolution of ischemic brain damage.
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PMID:Decreased protein kinase C activity during cerebral ischemia and after reperfusion in the adult rat. 223 Aug 6

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

Sequential alterations in the binding of [3H]cyclic AMP (cAMP) as an indicator of cAMP-dependent protein kinase (cAMP-DPK) binding activity following transient cerebral ischaemia were studied in the gerbil brain using receptor autoradiography. Transient ischaemia was induced for 10 min. [3H]cAMP binding in the stratum oriens and pyramidale of the hippocampal CA1 sector significantly decreased in the early post-ischaemic stage and showed severe reduction 7 days and 1 month after recirculation. By contrast, [3H]cAMP binding showed no significant alterations in the stratum radiatum of the hippocampal CA1 sector and the stratum pyramidale of the hippocampal CA3 sector up to 48 h after ischaemia. However, the binding in these areas significantly decreased 7 days and 1 month after ischaemia. The stratum lacunosum-moleculare of the hippocampal CA1 sector and dentate gyrus showed no significant changes in [3H]cAMP binding throughout the recirculation period. However, in the dorsolateral part of the striatum, where severe neuronal damage was seen morphologically, [3H]cAMP binding was significantly reduced only one month after ischaemia. These results indicate that marked alteration of intracellular signal transduction precedes neuronal damage in the hippocampal CA1 sector, but not in the striatum. Furthermore, our autoradiographic data suggest that post-ischaemic alteration in [3H]cAMP binding between the hippocampal CA1 sector and striatum may be produced by different mechanisms.
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PMID:Sequential changes of [3H]cyclic AMP binding in the gerbil brain following transient cerebral ischaemia. 810 69

We studied the alterations in binding of cyclic AMP as an indicator of particulate cyclic AMP-dependent protein kinase binding activity following transient cerebral ischemia in Mongolian gerbils and examined the effects of vinconate and pentobarbital against alterations in the binding. Animals were allowed to survive for 5 h and 7 days after 10 min of cerebral ischemia induced by bilateral occlusion of common carotid arteries. [3H]Cyclic AMP binding was significantly reduced in the hippocampus 5 h after ischemia, whereas the striatum showed no significant change in the binding. Seven days after ischemia, a severe reduction of [3H]cyclic AMP binding was noted in the dorsolateral striatum, hippocampal CA1 and CA3 sectors, and dentate gyrus. Intraperitoneal administration of vinconate (100 or 300 mg/kg) showed a significant elevation of [3H]cyclic AMP binding in the striatum, stratum pyramidale of hippocampal CA1 and CA3 sectors, and dentate gyrus 5 h after ischemia. By contrast, the intraperitoneal administration of pentobarbital (40 mg/kg) showed no significant alteration of [3H]cyclic AMP binding in most of these regions. However, vinconate and pentobarbital prevented a significant reduction of [3H]cyclic AMP binding in the dorsolateral striatum and stratum pyramidale of hippocampal CA3 sector 7 days after ischemia, although both drugs failed to prevent damage to the hippocampal CA1 sector. These results suggest that alteration in cyclic AMP binding may not be a major factor in causing ischemic neuronal damage.
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PMID:Changes of [3H]cyclic adenosine monophosphate binding in the gerbil brain following transient cerebral ischemia: an autoradiographic study and investigation of the effects of vinconate and pentobarbital. 838 51

We examined the sequential alterations in the binding of selective cyclic adenosine monophosphate (cAMP)-phosphodiesterase (PDE) and cAMP-dependent protein kinase (cAMP-DPK) in the gerbil brain following transient cerebral ischemia using in vitro quantitative autoradiography. [3H]Rolipram, a cAMP-PDE inhibitor, and [3H]cAMP were used to label cAMP-PDE and cAMP-DPK, respectively. Gerbils were subjected to 2-min or 6-min ischemia. Two-minute ischemia, which caused no morphological neuronal damage, produced no significant changes in either [3H]rolipram or [3H]cAMP binding throughout the recirculation period. The reduction of [3H]rolipram binding in the CA1 subfield of the hippocampus began 6 h after 6-min ischemia. Seventy percent of [3H]rolipram binding was preserved at 4 days, at which time almost all CA1 pyramidal cells had been destroyed. On the other hand, the reduction of [3H]cAMP-binding sites in the CA1 subfield began 1 day after 6-min ischemia. At 4 days, 47% of [3H]cAMP-binding sites in the CA1 subfield were preserved. Furthermore, we observed a transient reduction of [3H]cAMP binding in the dentate gyrus, which is resistant to ischemia, at 1 day and 4 days. These results indicate that marked alterations of cAMP-PDE and cAMP-DPK precede neuronal death in the hippocampal CA1 subfield, and the dentate gyrus also showed a transient alteration of cAMP-DPK.
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PMID:Sequential alterations of [3H]rolipram and [3H]cyclic adenosine monophosphate binding in the gerbil brain following transient cerebral ischemia. 838 73

Calmodulin-kinase II (CaM kinase) is a calcium/calmodulin-dependent protein kinase which is highly enriched in the nervous system and mediates many of calcium's actions. Regulation of CaM kinase activity plays an important role in modulating synaptic transmission, synaptic plasticity and in neuropathology. Primary regulation of CaM kinase occurs via changes in intracellular calcium concentrations. Increased calcium stimulates protein kinase activity and induces autophosphorylation. Autophosphorylation of CaM kinase at specific sites results in altered activity and responsiveness to subsequent changes in calcium concentrations. Intracellular translocation of CaM kinase also appears to result from autophosphorylation. These mechanisms of regulation play an important role in synaptic plasticity (e.g., Aplysia ganglia), status epilepticus and cerebral ischemia. Long-lasting alterations in the expression of CaM kinase have been demonstrated in the kindling model of epilepsy and in monocular deprivation and therefore modulation of gene expression, in addition to autophosphorylation and translocation, appears to be another important mechanism of regulating CaM kinase activity.
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PMID:Regulation of type-II calmodulin kinase: functional implications. 838 27


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