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

1. Activation of neutrophils results in increased tyrosine phosphorylation of several proteins that may have important roles in receptor/effector coupling. In this study, the effect of a protein tyrosine kinase inhibitor on receptor-mediated neutrophil activation by platelet-activating factor (PAF), leukotriene, B4 (LTB4) and N-formylmethionylleucylphenylalanine (FMLP) is investigated. 2. alpha-Cyano-3,4-dihydroxythiocinnamamide dose-dependently inhibited intracellular calcium release and superoxide generation from human neutrophils activated by 1 microM LTB4, PAF, and FMLP. 3. In the presence of cytochalasin B, FMLP stimulated elastase release from neutrophils was also inhibited to unstimulated levels by 5 min pretreatment with alpha-cyano-3,4-dihydroxythiocinnamamide. 4. The inhibitory action of alpha-cyano-3,4-dihydroxythiocinnamamide was found to be at or upstream of phospholipase C activation, blocking both phosphatidylinositol hydrolysis and protein kinase C activation. alpha-Cyano-3,4-dihydroxythiocinnamamide did not affect agonist receptor binding sites or receptor affinity in neutrophils. 5. Immunoblot analysis demonstrated the tyrosine phosphorylation of proteins of 41, 56, 66, and 104 kDa in neutrophils treated with agonists. Treatment of neutrophils with alpha-cyano-3,4-dihydroxythiocinnamamide prior to stimulation with chemoattractants reduced tyrosine phosphorylation of the above phosphoproteins. 6. These results indicate that alpha-cyano-3,4-dihydroxythiocinnamamide might be a useful agent in characterizing the essential proteins and biochemical pathways that regulate neutrophil activation.
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PMID:Inhibition of human neutrophil responses by alpha-cyano-3,4-dihydroxythiocinnamamide; a protein-tyrosine kinase inhibitor. 150 49

Trifluoperazine, a calmodulin antagonist, suppressed the clofibric acid-evoked induction of the peroxisomal cyanide-insensitive fatty acyl-CoA oxidizing system and carnitine acetyltransferase in rat liver and also in cultured rat hepatocytes. H-7, a potent inhibitor of protein kinase C, also suppressed the induction of these enzymes by clofibric acid, bezafibrate, Wyl4,643 or mono(2-ethylhexyl)phthalate in cultured rat hepatocytes. This suppressive effect was also confirmed by the protein composition of hepatocytes treated with clofibric acid and these antagonists, where the increase in the amount of peroxisomal bifunctional enzyme by peroxisome proliferator was markedly suppressed by above two antagonists. Profile of the time-dependent changes in the activities of the two enzymes after clofibric acid treatment showed that there might be two phases in the induction process. The initial phase (0-3 days after the treatment) showed a relative low inducing rate and subsequent phase (3-5 days after the treatment) showed an abrupt induction. The suppressive effect of the above two antagonists was significant in the later phase. In a time course study of the induction process of peroxisomal catalase, bifunctional enzyme or 69 kDa integral membrane protein using immunochemical detection, the induction of the membrane protein by clofibric acid was delayed compared with that of the bifunctional enzyme, where the induction was inhibited almost completely by nicardipine. These experimental results suggest that calmodulin- and protein kinase C-dependent processes play an important role in the process of marked induction of peroxisomal enzymes and membrane protein by drugs in rat liver.
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PMID:Involvement of calmodulin- and protein kinase C-related mechanism in an induction process of peroxisomal fatty acid oxidation-related enzymes by hypolipidemic peroxisome proliferators. 159 Dec 74

Platelet aggregation is mediated via binding of fibrinogen to sites on the membrane glycoprotein IIB-IIIA complex which become exposed when the cells are stimulated. We report here evidence of a dynamic and reversible exposure of binding sites for fibrinogen. In the absence of fibrinogen, exposed sites (B*) gradually lose their capacity to bind fibrinogen and close (Bo). On stimulation with platelet-activating factor (PAF, 500 nM) at 22 degrees C, closing of B* is enhanced by agents that raise cyclic AMP levels (10 ng of prostaglandin I2/ml; 5 mM-theophylline), inhibit protein kinase C (PKC; 25 microM-sphingosine; 1 microM-staurosporine), or disrupt the energy supply (30 mM-2-deoxy-D-glucose + 1 mM-CN-), or by raising the temperature to 37 degrees C. Conversely, activation of PKC 1 microM-1,2-dioctanoyl-sn-glycerol; 55 nM-phorbol 12-myristate 13-acetate) and an increase in intracellular [Ca2+] (100 nM-ionomycin + extracellular Ca2+) oppose the disappearance of B*. Phosphorylation of the 47 kDa protein illustrates the tight coupling between PKC and B* under all conditions tested, except when the cyclic AMP level is raised, and B* is converted to Bo without affecting PKC activity. Although the increase in PKC activity is much smaller with ADP or even absent upon stimulation with adrenaline, the control of B* is equally sensitive to modulation of cyclic AMP and PKC activity. We conclude that PAF, ADP and adrenaline regulate exposure of fibrinogen binding sites through a common mechanism consisting of two independent pathways, one dominated by PKC and the other by an as yet unidentified cyclic AMP-sensitive step.
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PMID:Protein kinase C and cyclic AMP regulate reversible exposure of binding sites for fibrinogen on the glycoprotein IIB-IIIA complex of human platelets. 184 26

In single NIH-3T3 fibroblasts loaded with fura-2, bombesin induced one of three patterns of increase in the concentration of intracellular free Ca2+ [( Ca2+]i): a single transient increase, a sustained increase, or repetitive transient increases in [Ca2+]i. Foetal-calf serum and ATP also gave these three patterns of response, although a lower proportion of cells gave repetitive Ca2+ transients in response to ATP. An increase in the concentration of bombesin from 1 to 25 nM increased the proportion of cells which exhibited repetitive Ca2+ transients. At 25 nM-bombesin, the proportion of cells which exhibited repetitive Ca2+ transients increased as the extracellular Ca2+ (Ca2+o) concentration was increased from 1 to 5 mM. Removal of Ca2+o by addition of EGTA, or inhibition of Ca2+ inflow by treatment of cells incubated in the presence of Ca2+o with verapamil or an activator of protein kinase C, abruptly terminated repetitive Ca2+ transients, with only one transient observed after the cessation of Ca2+ inflow. Repetitive Ca2+ transients were not observed in cells incubated in the absence of Ca2+o and in the presence of EGTA. Addition of Ca2+o to cells previously incubated in the presence of EGTA caused a resumption of repetitive Ca2+ transients. Addition of thapsigargin alone induced a large transient increase in [Ca2+]i, whereas much smaller transient increases in [Ca2+]i were induced in about 30% of cells tested by caffeine or carbonyl cyanide m-chlorophenylhydrazone (CCCP) plus oligomycin. Thapsigargin or the combination of CCCP plus oligomycin completely inhibited bombesin-induced repetitive Ca2+ transients, whereas caffeine had no effect. It is concluded from the studies of the role of Ca2+o that NIH-3T3 cells differ from other cell types in the anatomical or chemical links between extracellular Ca2+ and the intracellular stores involved in the generation of Ca2+ transients, whereas the results of the experiments with inhibitors indicate that the generation of repetitive Ca2+ transients in NIH-3T3 cells is unlikely to involve Ca(2+)-induced Ca2+ release from caffeine-sensitive stores.
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PMID:Inhibition of Ca2+ inflow causes an abrupt cessation of growth-factor-induced repetitive free Ca2+ transients in single NIH-3T3 cells. 191 Mar 37

The dynamics and mechanisms of extracellular release of hydrogen peroxide (H2O2) from bovine pulmonary artery endothelial cells (EC) subjected to anoxia, hypoxia, and hypoxia followed by reoxygenation were examined using various inhibitors of enzymatic systems in intact cells and by direct measurement of H2O2 production from isolated EC plasma membranes. Extracellular H2O2 was measured with a fluorometric assay. EC exposed to hypoxia (3% O2) and anoxia (0% O2) released less H2O2 (29.6 +/- 1.3% and 4.2 +/- 0.7%, respectively) compared with EC exposed to normoxia (20% O2). The extracellular release of H2O2 from EC previously exposed to hypoxia for 24 h increased immediately after reoxygenation (20% O2) to 272 +/- 48%, as compared with EC exposed continuously to normoxia (100% release). Inhibition of xanthine oxidase (XO) by allopurinol did not reduce the release of H2O2 from cells exposed to normoxia or hypoxia followed by reoxygenation. Furthermore, inhibitors of cyclooxygenase (indomethacin), phospholipase A2 (quinacrine and chlorpromazine), nitric oxide synthase (L-arginine analogs), the mitochondrial electron transport chain (rotenone and cyanide), and cytochrome P-450 (methoxypsoralen) had no or minimal effect on this release. On the other hand, inhibitors of protein kinase C (calphostin and staurosporine) and NADPH oxidase (diphenyliodonium) reduced the release of H2O2 from EC in a dose-dependent manner in both exposure groups. In separate experiments, plasma membranes isolated from EC were found to produce H2O2 in the presence of NADH or NADPH as electron donors. This was inhibited by diphenyliodonium but not by allopurinol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Release of hydrogen peroxide in response to hypoxia-reoxygenation: role of an NAD(P)H oxidase-like enzyme in endothelial cell plasma membrane. 752 30

We have examined the effect of pretreatment with a potent protein kinase C (PKC) inhibitor, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine (H-7), against metabolic alterations induced by sodium cyanide (NaCN), 4.2 mg/kg, in brain of anesthetized male micropigs (6-10 kg). Brain high energy phosphates were analyzed using a 31P nuclear magnetic resonance (NMR) spectroscopic surface coil in a 4.7 Telsa horizontal bore magnet. H-7, 1 mg/kg, was given intravenously (i.v.) 30 min before NaCN challenge (H-7 + CN-). Prior to NaCN, H-7, or H-7 + CN- administration, baseline 31P resonance spectra of 1-min duration were acquired for 5-10 min, and continued for an additional 60 min following i.v. NaCN injection, each animal serving as its own control. Peaks were identified as phosphomonoester (PME), inorganic phosphate (Pi), phosphodiester (PDE), phosphocreatine (PCr) and adenosine triphosphate (ATP), based on their respective chemical shifts. Without H-7 pretreatment, NaCN effects were marked by a rising Pi and a declining PCr peak 2 min after injection, with only 2/5 of the animals surviving the 60 min experiment. Through a pretreatment period of 30 min, H-7 did not affect baseline cell energy profile as reflected by the 31P-NMR spectra, but in its presence, those changes (i.e. diminishing PCr and rising Pi peaks) elicited by NaCN were markedly blunted; 4/5 of the animals in this group survived the NaCN challenge. It is proposed that H-7, a pharmacologic inhibitor of PKC, may be useful in CN- antagonism, underscoring the role of PKC in cyanide intoxication.
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PMID:A protein kinase C inhibitor attenuates cyanide toxicity in vivo. 762 70

The effect of potassium cyanide-induced chemical hypoxia on protein kinase C (PKC) translocation and cell injury was studied in differentiated PC12 cells. The cellular distribution of PKC in control cells and cells exposed to 100 microM and 1 mM KCN for 30 min. was visualized by use of an anti-PKC antibody and confocal laser scanning microscope. In control differentiated PC12 cells, PKC was localized perinuclearly, while following 12-phorbol 13-myristate acetate (PMA) or KCN it was translocated to the plasma and organelle membranes. Western blot analysis was used to quantify the translocation. Chemical hypoxia increased the membrane-bound PKC to 210% of control levels, while chelerythrine, a PKC inhibitor, and block of calcium influx into the cells (with calcium channel blocker and calcium-free medium) prevented this effect. Cyanide-induced PKC translocation persisted for at least 120 min. Cell injury was monitored by measuring lactate dehydrogenase (LDH) efflux from the cells 24 hr after addition of cyanide. PKC activation plays a role in hypoxic damage, since PKC down-regulation (by overnight exposure to PMA) or inhibition (with chelerythrine or staurosporine) conferred protection against KCN-induced cytotoxicity. Ca2+ channel blocker nifedipine also protected against chemical hypoxia. None of the pretreatments rendered complete protection against cyanide-induced hypoxia, indicating that PKC-independent mechanism(s) are also activated during chemical hypoxia and contribute to cell injury.
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PMID:Neuroprotective effects of PKC inhibition against chemical hypoxia. 779 71

A possible relationship among cyanide-induced convulsions, calmodulin, nitric oxide and protein kinase C was investigated in mice. The ED50 value of cyanide as measured by induction of tonic seizures was significantly increased in a dose-dependent manner when mercuric chloride (0.5 or 5.0 nmol/body), gangliosides (GGS) (90 nmol/body), a protein kinase C inhibitor or trifluoperazine (TFP) (45 or 90 nmol/body), a calmodulin inhibitor were preinjected intracerebroventricularly (i.v.t.) and NG-nitro-L-arginine (NNA) (300 mg/kg), a nitric oxide (NO) synthase inhibitor was preinjected intraperitoneally (i.p.) in mice. These results suggest that protein kinase C, calmodulin, and NO dependent cyclic guanosine monophosphate (GMP) dependent enzymes may contribute to the induction of convulsions. In contrast, 2,4-dinitrophenol (DNP) (50 nmol/body, intracerebroventricularly (i.v.t.), an uncoupler of oxidative phosphorylation significantly decreased the ED50 value of cyanide. In addition, DNP (100 nmol/body, i.v.t.) produced a severe tonic seizure in all of the treated mice. These indicate that adenosine triphosphate (ATP) depletion may also contribute in part to the development of cyanide-induced convulsions.
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PMID:A hypothesis for cyanide-induced tonic seizures with supporting evidence. 782 86

Activation and translocation of protein kinase C (PKC) during KCN-induced histotoxic hypoxia was studied in rat brain slices prepared from cerebellum, hippocampus, and cortex. Treatment with 1-10 mM KCN produced a significant increase in PKC translocation and enzyme activity in the particulate fraction of cerebellar and hippocampal slices. In cortical slices, PKC activity was not affected by cyanide treatment. The membrane-associated PKC activity reached a maximum 30 minutes after incubation with KCN and remained elevated up to 60 minutes in both the hippocampus and cerebellum. Pretreatment with MK-801 and APV, specific NMDA receptor antagonists, blocked the cyanide-stimulated translocation in the hippocampus and cerebellum, whereas CNQX, an AMPA/kainate receptor antagonist, did not alter the response. These results demonstrate that cyanide stimulates PKC activation and translocation from the cytosol to membranes in select brain areas and NMDA receptor activation mediates this process.
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PMID:Cyanide induces protein kinase C translocation: blockade by NMDA antagonists. 785 58

Detoxification of cyanide is catalyzed by a sulfurtransferase, rhodanese, a phosphoprotein regulated by unknown protein kinases. In this study, we determined if a Ca2+/phospholipid-modulated phosphotransferase, protein kinase C (PKC) could modify rhodanese activity. Thiocyanate (SCN-) production as an estimate of rhodanese activity in vitro was measured in the presence or absence of exogenously added purified PKC, or 12-O-tetradecanoylphorbol acetate (TPA), a pharmacologic activator of the endogenous PKC. HI-6 (1-(2-(hydroximino)methyl))pyridinium-2-(4-(aminocarbonyl) pyridinium dimethylether) is an oxime that may dephosphorylate phosphoproteins due to the proposed phosphatase-like activity of the oximes. We examined HI-6's effect on rhodanese-catalyzed SCN- production. Bovine kidney rhodanese (0.40 mg/ml protein) was reacted with 4 mM KCN and SCN- production determined spectrophotometrically following the method of Westley (1981). Preincubating rhodanese with 20 or 100 ng of purified PKC (alpha, beta, gamma isozymes) for 5 min before initiating the reaction with 4 mM KCN as the substrate increased SCN- production by 17 or 40%, respectively, over the control (P < 0.05). Rhodanese formation of SCN- decreased when the preincubation was conducted with 1 nM or 100 nM of TPA. With HI-6 at 1 or 10 microM used in place of PKC, or TPA, rhodanese activity was increased by 6 or 14% (P < 0.05), respectively, compared to control. Under the conditions examined, exogenous PKC acting as a possible phosphate acceptor, and HI-6, a potential dephosphorylating compound, increased rhodanese activity. These data are consistent with the observation that rhodanese can exist as a phosphorylated enzyme which is not active and a dephosphorylated form which is active. It is suggested that addition of purified, exogenous PKC may accept phosphate from phosphorylated rhodanese or HI-6 may dephosphorylate rhodanese, both of which stimulate the conversion of cyanide anion to the less toxic SCN-. These observations support the possibility that rhodanese may be regulated by protein phosphorylation and treatments that alter the phosphorylation state of rhodanese may affect cyanide detoxification via SCN- formation.
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PMID:Protein kinase C modulation of rhodanese-catalyzed conversion of cyanide to thiocyanate. 788 66


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