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)

The protective effects of protein kinase inhibitors and a calmodulin kinase inhibitor (W-7) against ischemic neuronal damage were examined in the CA1 subfield of the hippocampus. Staurosporine, KT5720, and KT5822 were used as inhibitors of protein kinase C (PKC), cyclic AMP-dependent protein kinase, and cyclic GMP-dependent protein kinase, respectively. All test compounds were injected topically into the CA1 subfield of the hippocampus. In the gerbil ischemia model, staurosporine (0.1-10 ng) administered 30 min before ischemia prevented neuronal damage in a dose-dependent manner. However, KT5720, KT5822, and W-7 were ineffective, even at a dose of 10 ng. In the rat ischemia model, staurosporine (10 ng) also prevented neuronal damage when administered before ischemic insult, although staurosporine administered 10 or 180 min after recirculation was ineffective. These results suggest the involvement of PKC in CA1 pyramidal cell death after ischemia and that the fate of vulnerable CA1 pyramidal cells through PKC-mediated processes could be determined during the early recirculation period.
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PMID:Staurosporine, a novel protein kinase C inhibitor, prevents postischemic neuronal damage in the gerbil and rat. 238 38

The influence of transient forebrain ischemia on the temporal alteration of protein kinase C (PKC) activity in the rat hippocampus was analyzed by quantitative autoradiography using [3H]phorbol 12,13-dibutyrate [( 3H]PDBu). As reported previously, the grain density was highest in the strata oriens and radiatum in the CA1 subfield. After transient forebrain ischemia (20 min), the [3H]PDBu binding in the CA1 subfield gradually increased during early recirculation, and became maximum 6-12 h after ischemia, when no microscopic damage of the CA1 pyramidal cells was obvious. Thereafter, grain density decreased and binding activity in the CA1 was lost by approximately 40% 7 days after ischemia, when CA1 pyramidal cells had become necrotic. This indicated a close association of phorbol ester binding sites with CA1 pyramidal cells. By contrast, [3H]PDBu binding sites were unchanged in the stratum radiatum in the CA3 throughout the recirculation, although the number of binding sites in the stratum oriens of the CA3 was decreased during early recirculation period. Seven days after recirculation, in the molecular layer of the dentate gyrus, where granule cells remained intact, [3H]PDBu binding activity increased by 33%, with a higher grain density in the inner region (supragranular layer). These results suggest that enhancement of PKC activity and/or translocation of the enzyme play an important role in the postischemic modulation of synaptic efficacy in the hippocampal formation and neuronal death of CA1 pyramidal cells.
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PMID:Protein kinase C activity in the rat hippocampus after forebrain ischemia: autoradiographic analysis by [3H]phorbol 12,13-dibutyrate. 270 52

The effect of the protein kinase C enzyme inhibitor H-7 was examined on the brain edema formation evoked by bilateral occlusion of the common carotid arteries in Sprague-Dawley rats of CFY strain. Brain edema was assessed by measurement of water and electrolyte contents of the brain. The results showed that pretreatment with H-7 reduced the extent of brain edema formation in a dose-dependent manner. The fact that H-7 treatment prevented the accumulation of water and certain electrolytes in the brain indicates that the protein kinase C may be activated not only in the neuronal structures but also in the microvessels during ischemia, which can lead directly or via certain calcium-mediated mechanisms to the opening of tight junctions resulting in the development of brain edema.
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PMID:Inhibition by H-7 of the protein kinase C prevents formation of brain edema in Sprague-Dawley CFY rats. 275 20

The role of protein kinase C (C kinase) in the left ventricular relaxation impaired by global ischemia was investigated in anesthetised dogs. Left ventricular global ischemia model was made by coronary blood flow reduction and atrial pacing (100-180 beats/min). By this maneuver, the time constant T and left ventricular end-diastolic pressure (LVEDP) were increased in a pacing-rate dependent manner. Intracoronary infusion of H-7, an inhibitor of C kinase, suppressed the magnitudes of the increments of T and LVEDP, while intracoronary infusion of 12-O-tetradecanoyl-phorbol-13-acetate, an activator of C kinase, enhanced the increases of T and LVEDP caused by ischemia. In non-ischemic group, H-7 did not influenced T and LVEDP. The results indicate that C kinase is activated by myocardial ischemia and enhances impairment of left ventricular relaxation.
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PMID:[The role of protein kinase C in left ventricular relaxation impaired by global ischemia]. 278 Nov 57

Marked changes in the intracellular localization of brain protein kinase C are evident after global ischemia generated by the restriction of the placental blood flow in the near-term rat embryo. A rapid (5 min) ischemia-dependent translocation of the enzyme from the cytosol to the particulate membrane fraction, which is completely reversible upon reperfusion, is observed. After 30 min of ischemia, substantial losses in protein kinase C activity and content as measured by [3H]phorbol dibutyrate binding are apparent. This is accompanied by a marked increase of a Ca2+-phosphatidylserine-independent kinase activity, already evident after 5 min of ischemia. By 15 or 30 min the total activity of the latter enzyme is equally distributed between the particulate and the cytosol fractions and is more than 3-fold higher in ischemic in comparison to naive animals. Activation and possible deregulation of protein kinase C are proposed to represent an initial step in the pathophysiology of brain ischemia.
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PMID:Protein kinase C alterations in the fetal rat brain after global ischemia. 319 27

We have reported that cardiac preconditioning against ischemia-reperfusion (IR) can be induced by transient ischemia (TI) and alpha 1-adrenoreceptor stimulation, both mediated by protein kinase C (PKC) (Mitchell, M., X. Meng, C. Parker, E. Brew, A. Harken, and A. Banerjee. Circ. Res. 76: 73-81, 1995). Our study objective was to explore the mechanism of endogenous preconditioning and address the role of PKC activation in bradykinin-mediated cardiac functional protection. Isolated rat heart was used to assess the effects of exogenous bradykinin, TI, selective B2-receptor blocker, and PKC antagonism on cardiac functional recovery after a global IR injury. Final recovery of developed pressure was improved in hearts treated with bradykinin and TI compared with controls. Bradykinin- and TI-mediated preconditioning was eliminated with coinfusion of the B2-receptor antagonist. Further evaluation of bradykinin-mediated preconditioning revealed that PKC blockade also eliminated functional protection. Immunofluorescent stains of bradykinin-treated hearts demonstrated translocation and activation of specific PKC isoforms in the preconditioned heart. We conclude that TI-mediated preconditioning involves intrinsic cardiac bradykinin receptor stimulation. Bradykinin, through the B2 receptor, initiates a series of intracellular events culminating in the activation of PKC.
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PMID:Role of bradykinin in cardiac functional protection after global ischemia-reperfusion in rat heart. 748 70

Both ischemia and hypoxia increase adenosine production in the heart. This study tested whether hypoxia increases adenosine production in the coronary artery via ecto-5'-nucleotidase and the role of protein kinase C in this condition. Canine left circumflex coronary artery was rapidly removed and incubated in 10 mL Krebs-Henseleit solution for 30 minutes. The Krebs-Henseleit solution contained 5'-iodotubercidin and 2'-deoxycoformycin, which inhibit adenosine kinase and adenosine deaminase, respectively. Adenosine production was measured in intact coronary arteries under normoxic conditions (16.2 +/- 1.2 pmol/mg protein). Adenosine production was reduced by 27% after removal of endothelium. Ecto-5'-nucleotidase activity of coronary arteries with and without endothelium was 51 +/- 6 and 41 +/- 4 nmol/mg protein per minute under normoxic conditions. Hypoxia increased adenosine production to 27.0 +/- 2.3 and 20.0 +/- 0.8 pmol/mg protein with and without endothelium. Hypoxia also increased ecto-5'-nucleotidase activity of coronary arteries with and without endothelium (74 +/- 8 and 53 +/- 5 nmol/mg protein per minute; P < .05). Increases in adenosine production under hypoxic conditions were blunted by both an inhibitor of ecto-5'-nucleotidase and inhibitors of protein kinase C. Activation of ecto-5'-nucleotidase was blunted by an inhibitor of protein kinase C. These results indicate that hypoxia increased extracellular adenosine production and activated ecto-5'-nucleotidase via activation of protein kinase C in coronary arterial smooth muscle and endothelial cells. Increased adenosine production in coronary arteries during hypoxia may contribute to coronary vasodilation and cardioprotection against ischemic injury.
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PMID:Activation of protein kinase C increases adenosine production in the hypoxic canine coronary artery through the extracellular pathway. 748 56

Both experimental traumatic brain injury and clinical traumatic brain injury appear to render the brain more vulnerable to a second ischemic insult. The mechanisms of enhanced vulnerability to subsequent ischemia appear to include a reduced ability to increase cerebral blood flow in response to hypotension, hypoxemia, or acute anemia and increased tissue sensitivity to ischemia. Although numerous mediators may be involved in increased tissue sensitivity, those that particularly merit investigation include oxygen free radicals, glutamate, arachidonate metabolites, calcium ions, and protein kinase C.
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PMID:Enhanced vulnerability to secondary ischemic insults after experimental traumatic brain injury. 749 45

Adenosine is released during brain ischemia and provides neuroprotection by actions on nerve and glial cells. Activation of the adenosine A1 receptor enhances the K+ and Cl- conductance in neurons, leading to membrane hyperpolarization and postsynaptic reduction of neuronal Ca2+ influx through voltage- and NMDA receptor-dependent channels. In addition adenosine A1 receptor activation decreases excitatory amino acid release, possibly via inhibition of N- and P-type Ca2+ channels. The A1 and A2 receptors, coupled to Gi/G(o) and Gs proteins respectively, often co-exist and interact with the phospholipase C-dependent activation of the protein kinase C and the adenylyl cyclase. Activation of the A1 receptor may mimic metabotropic receptor stimulation in activating intracellular Ca2+ mobilization and PKC. A2 receptor mediated cAMP formation is depressed by high intracellular Ca2+ but enhanced by PKC activation. By modulating these metabolic signaling events, adenosine may influence acute cell functions, gene transcription and sustained changes of nerve and glial cells relevant for the development of ischemic damage. The neuroprotective adenosine effect seems to be amplified by treatment with propentofylline, which enhances adenosine release, influences the balance between A1 and A2 receptor mediated actions, depresses the free radical formation in activated microglia and influences astrocyte reactions.
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PMID:Modulation of nerve and glial function by adenosine--role in the development of ischemic damage. 753 56

The potential involvement of platelet activating factor (PAF, 1-O-alkyl 2-O-acetyl-sn-glycero-3-phosphocholine) in aggravation of ischemic brain injury has been recently postulated. Reported evidences in support of this thesis include increases of brain PAF concentration during ischemia and the neuroprotective effect exerted by PAF antagonists. In this article, we demonstrate that several PAF-mediated biochemical responses in synaptoneurosomes in vitro resemble these observed previously in ischemic brain and are widely acknowledged as the potentially causal factors in this pathology. In synaptoneurosomes prepared from rat hippocampus, 10 nM PAF caused an observable elevation of intracellular calcium as measured by fluorescence Fura-2A probe. A similar elevation of synaptoneurosomal [Ca2+]i was evoked by 1 mM glutamate treatment. As an effect of calcium entry after PAF application, a translocation of protein kinase C (PKC) toward plasma membranes was demonstrated by 3H-labeled phorbol-binding method. It was followed by an increase of 50 kDa proteolytic fragment of the enzyme (PKM) recognized on Western blots with anti-PKC antibody. Incubation of synaptoneurosomes in the presence of calcium chelators abolished these effects of PAF and significantly decreased the content of PKC in the membranes. Furthermore, PAF treatment markedly attenuated the receptor- and postreceptor-activated cAMP accumulation in synaptoneurosomes. The decrease of cAMP level seems to be secondary to the PAF-induced calcium entry with subsequent activation of cAMP-specific phosphodiesterase, since it was completely blocked by IBMX, a potent inhibitor of this enzyme. Our observations indicate that PAF in a concentration found in ischemic brain can elevate [Ca2+]i and potentiate calcium-dependent intracellular signalling in synaptoneurosomes in vitro, including PKC translocation/activation and proteolysis, followed by IBMX-sensitive inhibition of cAMP production. The relative contribution of these events to ischemic brain injury is currently under extensive investigation.
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PMID:Modulation of signal transduction in rat synaptoneurosomes by platelet activating factor. 754 18


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