Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate, an excitatory amino acid (EAA), plays an important role in neuron to neuron signaling by binding to specific receptors. When, during neuronal firing, quanta of glutamate are released from the nerve terminal, they interact with the receptors for a few milliseconds and, thereafter, glutamate is promptly cleared by appropriate mechanisms. The neurotoxic action of glutamate arises from its capacity to trigger a pathophysiological chain of events when it acts continuously and abusively on its receptors (e.g., during cerebral edema associated with trauma, ischemia, stroke). In primary cultures of cerabellar granule neurons the abusive stimulation of EAA receptors by glutamate amplifies pathologicaly two early intracellular signals: free cytosolic Ca++ and the translocation of protein kinase C (PKC) from cytosol to neuronal membrane. Both of these signals persist unabated even after removal of glutamate from the incubation medium. Natural gangliosides and their semisynthetic derivatives protect neurons from glutamate toxicity by blocking the consequences of receptor abuse but they leave physiological responses to glutamate unaffected; hence they represent a prototype of a "receptor abuse dependent antagonist" (RADA).
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PMID:Ganglioside-mediated protection from glutamate-induced neuronal death. 198 78

Alterations of the second-messenger systems, adenylate cyclase (AC) and protein kinase C (PKC), and local cerebral blood flow (lCBF) were evaluated during experimental cerebral ischemia in gerbils employing a quantitative autoradiographic method, which permitted these three parameters to be measured in the same brain. Ischemia was induced by occlusion of the right common carotid artery for 6 h. Animals attaining more than 5 in their ischemic scores were utilized for further experiments. At the end of ischemia, lCBF was measured by the [14C]iodoantipyrine method. The AC and PKC activities were estimated by the autoradiographic technique developed in our laboratory using [3H]forskolin (FK) and [3H]phorbol-12,13-dibutyrate (PDBu), respectively. The lCBF fell below 10 ml/100 g/min in most cerebral regions on the ligated side. The greatest reduction in FK binding was noted in the olfactory tubercle, caudate-putamen, and globus pallidus, followed by the hippocampus and cerebral cortices. The FK binding tended to be low at lCBF less than 20 ml/100 g/min in the cerebral cortices. However, the PDBu binding was relatively well preserved in each cerebral structure, and no significant correlation between lCBF and PDBu binding was noted in the cerebral cortices. The AC system may thus be vulnerable to ischemic insult over extensive brain regions, while the PKC system may be relatively resistant to ischemia.
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PMID:Autoradiographic analysis on second-messenger systems and local cerebral blood flow in ischemic gerbil brain. 199 99

The changes in the levels of protein kinase C [PKC(alpha, beta II, gamma)] were studied in cytosolic and particulate fractions of striatal homogenates from rats subjected to 15 min of cerebral ischemia induced by bilateral occlusion of the common carotid arteries and following 1 h, 6 h, and 48 h of reperfusion. During ischemia the levels of PKC(beta II) and -(gamma) increased in the particulate fraction to 390% and 590% of control levels, respectively, concomitant with a decrease in the cytosolic fraction to 36% and 20% of control, respectively, suggesting that PKC is redistributed from the cytosol to cell membranes. During reperfusion the PKC(beta II) levels in the particulate fraction remained elevated at 1 h postischemia and decreased to below control levels after 48 h reperfusion, whereas PKC(gamma) rapidly decreased to subnormal levels. In the cytosol PKC(beta II) and -(gamma) decreased to 25% and 15% of control levels at 48 h, respectively. The distribution of PKC(alpha) did not change significantly during ischemia and early reperfusion. The PKC activity in the particulate fraction measured in vitro by histone IIIS phosphorylation in the presence of calcium, 4 beta-phorbol 13-myristate 12-acetate, and phosphatidylserine (PS) significantly decreased by 52% during ischemia, and remained depressed over the 48-h reperfusion period. In the cytosolic fraction PKC activity was unchanged at the end of ischemia, and decreased by 47% after 6 h of reperfusion. The appearance of a stable cytosolic 50-kDa PKC-immunoreactive peptide or an increase in the calcium- and PS-independent histone IIIS phosphorylation was not observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in the activity of protein kinase C and the differential subcellular redistribution of its isozymes in the rat striatum during and following transient forebrain ischemia. 200 38

Acute forebrain ischemia reduced protein kinase C (PKC) activity in the adult rat cortex, striatum and hippocampus by 60-70% after 20 min ischemia episodes, followed by 48 h of recirculation. Ischemia of 1 min, followed by recirculation, produced a less pronounced but significant decrease in PKC activity. The ischemia-induced decrease of PKC affected both the soluble and the membrane-bound kinase. Alterations of PKC predate neuronal death following ischemia.
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PMID:Reduction of protein kinase C activity in the adult rat brain following transient forebrain ischemia. 202 20

Excessive Ca2+ influx through NMDA receptor-coupled channels has been linked to neuronal cell death. Using an in vitro model of transient brain ischemia, we investigated possible protective effects of NMDA receptor antagonists ketamine or MK-801 and of calmidazolium, an inhibitor of intracellular Ca2(+)-activated proteins. Brain ischemia/recovery was simulated in isolated hippocampal slices and injury monitored by measurement of ATP levels. Omission of both glucose and oxygen (but not oxygen alone) for 20 min led to persistent ATP deficits after 4 h recovery. Addition of ketamine or MK-801 at 1 microM permitted ATP to recover within 1 h, as did addition of calmidazolium at 10 microM. Our findings are consistent with other reports that NMDA receptor antagonists can protect neuronal tissue from ischemic damage. The role of inappropriately activated Ca2(+)-mediated signaling processes in the mechanism(s) of such injury is suggested by the protection also seen with calmidazolium, an inhibitor of calmodulin and other structurally related proteins such as calpain(s) and protein kinase C. The inhibition of intracellular Ca2+ target proteins may be an alternative for protection of the brain against injury due to insults that activate NMDA receptors.
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PMID:Ischemic brain injury in vitro: protective effects of NMDA receptor antagonists and calmidazolium. 214 19

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

Complete obstruction of the maternal blood flow to fetal rats at 20 days of gestation for a period of 10 min causes a significant shift of approximately 22% in protein kinase C (PKC) activity from a cytosolic to a membrane-bound form in the fetal brain. This translocation can be entirely reversed without losses in activity by a single intraperitoneal injection into the gravid rat of either a mixture of disialo- and trisialoganglioside [polysialoganglioside (PSG)] or by GM1 (50 mg/kg of body weight) given 3 h before onset of the ischemic episode. Cessation of blood flow for 15 min followed by a reperfusion period of 24 h results in a 47% loss in total PKC activity. This down-regulation can be almost entirely prevented upon intraperitoneal administration of GM1 3 h before, but also during and even 90 min after the onset of ischemia. The PSG mixture is also effective, particularly when given 3 h before the insult. Down-regulation of PKC is accompanied by an increase in a Ca2(+)-phosphatidylserine-independent kinase [protein kinase M (PKM)] activity, which rises from 30 pmol/min/mg of protein in control animals to a maximal value of 83.1 pmol/min/mg of protein after 15 min of ischemia and 6 h of reperfusion. By 24 h, PKM activity is 46.8 pmol/min/mg of protein. Administration of GM1 blocks completely the appearance of PKM, a result suggesting that PKC down-regulation and PKM activity elevation are intimately associated events and that both are regulated by GM1 ganglioside.
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PMID:Gangliosides prevent ischemia-induced down-regulation of protein kinase C in fetal rat brain. 223 Aug 13

Many investigations have shown that calcium and adenosine triphosphate are crucial to central nervous system functions. It is probable that alterations of these substances during central nervous system ischemia are involved in the processes that cause irreversible neural damage. Calcium regulates several protein kinases that are responsible for phosphorylation of proteins vital for many central nervous system functions. Using a rabbit spinal cord ischemia model, we found protein kinase C and calcium/calmodulin-dependent kinase were severely affected during the first hour of ischemia. Protein kinase A was not significantly affected. The time course of lost protein kinase C enzyme activity closely corresponded to irreversible loss of neurologic function, and there is evidence that protein kinase C inhibitor activity is generated. Also, drugs that inhibit protein kinase C increased neurologic damage when administered during the early phases of ischemia. These results suggest that protein phosphorylation, particularly by protein kinase C, is critical to maintenance of neurologic function.
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PMID:Protein phosphorylation during ischemia. 223 67

The subcellular distribution of PKC(alpha) and PKC(gamma) was studied in homogenates of cerebral cortex from rats subjected to 10 and 15 min of ischemia and 15 min of ischemia followed by 1 h, 6 h, 24 h, 48 h, and 7 days of reperfusion. During ischemia no significant changes in the levels of PKC (alpha) were seen. During the first hour of reperfusion, a transient 2.5-fold (P less than 0.05) increase in PKC (alpha) levels was observed in the particulate fraction. In contrast, a three-fold increase of PKC(gamma) in the particulate fraction concomitant with a 40% decrease in the cytosol was noted during ischemia. In the postischemic phase the levels in the cytosol decreased to 35% of control values at 2 days following ischemia, with a concomitant decrease in the particulate fraction to control levels. The redistribution of PKC to the cell membranes during and following ischemia could be due to ischemia induced receptor activation, increased levels of diacylglycerols, arachidonate and intracellular calcium, and may be of importance for the development of ischemic neuronal damage.
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PMID:Protein kinase C is translocated to cell membranes during cerebral ischemia. 228 Aug 99

The influence of transient forebrain ischemia on the temporal alteration of protein kinase C (PKC) activity in the gerbil hippocampus was analyzed by quantitative autoradiography using [3H]phorbol 12,13-dibutyrate (PDBu). The [3H]PDBu binding activity in the stratum oriens of the CA1 subfield increased at 6 h after ischemia, but the binding activity in this subfield decreased at 7 days after ischemia. In contrast, the [3H]PDBu binding activity increased in the molecular layer of the dentate gyrus at 7 days after ischemia. Pre-treatment of pentobarbital prevented an increase in the [3H]PDBu binding activity in the stratum oriens of the CA1 subfield at 7 days after ischemia. These results indicate the possibilities that PKC may play a pivotal role in the post-ischemic neuronal damage in the hippocampal CA1 subfield.
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PMID:Protein kinase C activity in the gerbil hippocampus after transient forebrain ischemia: morphological and autoradiographic analysis using [3H]phorbol 12,13-dibutyrate. 229 82


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