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)

Effects of ethanol on the function of Ca(2+)-activated Cl- channels activated by G protein-coupled serotonin (5-hydroxytryptamine, (5-HT)1c) and muscarinic M1 cholinergic receptors were studied in Xenopus oocytes expressing mouse whole-brain mRNA. Ethanol (25-200 mM) inhibited currents evoked by both 5-HT and acetylcholine (ACh), in a concentration-dependent manner. The maximal effect was obtained with 150 mM ethanol, which produced 65 and 49% inhibition of 5-HT and ACh responses, respectively. In the presence of 100 mM ethanol, the EC50 values for both 5-HT and ACh were increased about 4-fold. In contrast, in oocytes expressing rat cerebellar mRNA, metabotropic glutamate receptor responses were much less sensitive to ethanol. To examine potential postreceptor sites for ethanol inhibition, guanosine-5'-O-(3-thio)triphosphate and myo-inositol-1,4,5-trisphosphate were injected intracellularly. Ethanol (100 mM) did not significantly inhibit the currents produced by either guanosine-5'-O-(3-thio)triphosphate or myo-inositol-1,4,5-trisphosphate. Activation of protein kinase C (PKC) by phorbol-12-myristate-13-acetate markedly inhibited 5-HT-induced responses. Both the PKC inhibitor peptide and staurosporine prevented ethanol inhibition of 5-HT-induced responses. Moreover, ethanol, similarly to phorbol-12-myristate-13-acetate and opposite to PKC inhibitors, enhanced the rate of Ca(2+)-activated Cl- current desensitization induced by repeated applications of 5-HT. These results indicate that certain types of receptor-G protein interactions are more susceptible than others to uncoupling by ethanol and that ethanol inhibition of 5-HT1c receptors requires PKC-mediated phosphorylation. We suggest that ethanol may activate PKC, which phosphorylates the receptors, resulting in inhibition of the responses.
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PMID:Ethanol inhibits the function of 5-hydroxytryptamine type 1c and muscarinic M1 G protein-linked receptors in Xenopus oocytes expressing brain mRNA: role of protein kinase C. 819 90

Ethanol inhibits N-methyl-D-aspartate (NMDA)-stimulated increases in intracellular Ca2+ in cerebellar granule cells apparently by reducing the potency of glycine to act as a co-agonist at the NMDA receptor. The inhibitory effect of ethanol on the NMDA response in these cells can be reversed not only by a high concentration of glycine, but also by the protein kinase inhibitors, staurosporine and calphostin C. We previously showed that activation of protein kinase C in cerebellar granule cells also resulted in inhibition of the NMDA response, and in decreased potency of glycine at the NMDA receptor. Furthermore, the inhibitory effects of ethanol and protein kinase C activation are not additive. These results suggest a role for protein kinase C in ethanol inhibition of NMDA responses in cerebellar granule cells. In contrast, although ethanol can inhibit the response to kainate in these cells in a "competitive" manner, this response is not affected by activation of protein kinase C.
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PMID:Involvement of protein kinase C in ethanol-induced inhibition of NMDA receptor function in cerebellar granule cells. 819 31

We studied the degranulation reaction of electropermeabilized human neutrophils induced by 1,2-didecanoyl-3-sn-phosphatidic acid (PA10). PA10 dose-dependently induced the release of beta-glucuronidase, an enzyme of azurophil granules, but did not induce the release of lactoferrin, a protein of specific granules. The enzyme release by PA10 absolutely required Ca2+, ATP, and Mg2+ and the concentrations for the half-maximal response were 2.5 microM, 60 microM, and 0.25 mM, respectively. Although Ca2+ alone at concentrations higher than 10 microM induced the release of both beta-glucuronidase and lactoferrin, the extents of the release were far less than that of the beta-glucuronidase release by PA10. Phorbol myristate acetate (PMA) and 1-oleoyl-2-acetyl-sn-glycerol induced the release of lactoferrin alone at concentrations of Ca2+ below 0.5 microM while they induced the release of both beta-glucuronidase and lactoferrin at higher Ca2+ concentrations, indicating that the degranulation induced by PA10 is not mediated by diacylglycerol which might be formed from PA. The degranulation reactions induced by PA10 and PMA were dose-dependently inhibited by staurosporine and calphostin C, protein kinase C inhibitors, although no direct activation of protein kinase C by PA10 was observed. The extent of the beta-glucuronidase release by PA10 was not enhanced by the addition of PMA. Propranolol, which inhibits protein kinase C as well as phosphatidic acid phosphohydrolase, strongly inhibited the degranulation reactions induced by PA10 and PMA. Ethanol, a metabolic modulator of phospholipase D, and cyclic AMP did not affect the degranulation reactions by PMA and PA10.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphatidic acid induces the release of beta-glucuronidase but not lactoferrin from electropermeabilized human neutrophils. 820 72

Studies on electropermeabilized human platelets indicated that any two of three distinct factors must be present for marked secretion of dense or alpha-granule constituents to occur. These factors are Ca2+, activation of protein kinase C (PKC) and activation of an unidentified GTP-binding protein ('GE'). Thus, in the absence of Ca2+, phorbol ester and GTP[S] acted synergistically to promote secretion, whereas in the presence of Ca2+, either activation of PKC or addition of GTP[S] was sufficient. In all cases, secretion correlated with the activation of phospholipase D (PLD), as detected by the formation of [3H]phosphatidic acid (PA) in the absence of ethanol or of [3H]phosphatidylethanol (PEt) in the presence of ethanol. Secretion did not correlate with phospholipase C (PLC) activity or with the accumulation of 1,2-diacylglycerol (DAG), both of which required Ca2+ and were inhibited by phorbol ester. Ethanol partially inhibited secretion in the absence of Ca2+. BAPTA, a known inhibitor of Ca(2+)-independent secretion in permeabilized cells, caused parallel inhibitions of secretion and PLD activity. GTP[S] enhanced PKC activity, as indicated by pleckstrin phosphorylation, apparently by stimulating the formation of PA in the absence of Ca2+, as well as of DAG in the presence of Ca2+. PA and stable analogues, including PEt, stimulated the Ca(2+)-independent phosphorylation of pleckstrin and other proteins in platelet supernatant fraction. The results suggest that PA formed by activation of PLD may mediate secretion from permeabilized platelets by PKC-dependent and independent mechanisms. However, in intact platelets stimulated by thrombin, PLD accounted for only 10-20% of the total PA formed and can only play a major role in secretion if this PA fraction is distinct from that formed by the combined actions of PLC and DAG kinase.
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PMID:Evidence that activation of phospholipase D can mediate secretion from permeabilized platelets. 820 83

Activation of phospholipase D (PLD) by receptor-coupled stimuli (vasopressin, ATP), phorbol esters, and Ca2+ ionophores was studied in isolated rat hepatocytes, double labeled with [3H]arachidonate and [14C]stearate. Phosphatidylethanol (Peth) was formed when cells were stimulated in the presence of ethanol. The effect of combinations of agonists was not additive, indicating that the same PLD isozyme(s) were activated. With all agonists, the 3H- and 14C-specific radioactivity in Peth was higher than in any of the main phospholipid classes. The 3H/14C ratios of Peth and phosphatidylcholine (PC) were identical and differed from other phospholipid classes, indicating that the predominant PLD substrate was a PC pool labeled preferentially with radioactive fatty acids. Ethanol (50-300 mM) decreased the initial rate of phosphatidic acid (PA) formation, but did not affect total PLD activity. Agonist-induced changes in steady state accumulation of PA or 1,2-diacylglycerol were also unaffected. A slow degradation of Peth (apparent t1/2 > 60 min) occurred after ethanol removal from cells prestimulated with vasopressin. The rate of degradation was unaffected by agonists that stimulate PLD. Thus, Peth formation is a suitable cumulative indicator for PLD activation in intact hepatocytes. Peth accumulation declined over a period of 5-20 min, depending on the agonist. The decline was not due to increased Peth degradation, or limitations in substrate supply to PLD, or enzyme inhibition by accumulated Peth. Instead, a homologous desensitization of PLD occurs with all agonists. This desensitization may involve the action of selective protein kinase C isozymes.
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PMID:Activation and desensitization of phospholipase D in intact rat hepatocytes. 828 37

Activation of RBL-2H3 cells by cross-linking their IgE receptors resulted in a biphasic increase in cellular 1,2-diacylglycerol (DG) content. The first-phase DG production was coincident with a transient breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2). The second large sustained phase of DG accumulation appeared to be derived mainly from phosphatidylcholine (PC) and partly from phosphatidylinositol (PI). The accumulation of phosphatidylethanol (PEt) and the reduction of DG formation in the presence of ethanol suggested that more than 50% of the DG due to PC hydrolysis was formed through the action of phospholipase D. The addition of phorbol myristate acetate or Ca2+ ionophore A23187 stimulated the hydrolysis of PC. In protein kinase C (PKC) down-regulated cells, PC hydrolysis induced by A23187 was markedly suppressed. Taken together, these results lead as to speculate that hydrolysis of PC is regulated by the increase in cellular Ca2+ and PKC activation through the hydrolysis of PIP2. The exocytotic response became evident with a 1 min time lag after antigen (Ag) stimulation, followed by the transient breakdown of PIP2. Ethanol inhibited Ag-stimulated serotonin secretion. The concentration-dependent inhibitory profile of secretion by ethanol correlated well with that of the sustained phase of DG accumulation. These results suggest that sustained DG production, mainly derived from PC through phospholipase D action, plays an important role in maintaining secretory response.
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PMID:[IgE-receptor stimulation induces biphasic 1,2-diacylglycerol production in RBL-2H3 cells. Phosphatidylcholine hydrolysis by phospholipase D plays a major role in the second sustained 1,2-diacylglycerol accumulation]. 845 68

Human circulating lymphocytes were isolated and incubated with ethanol. Cytosolic, membrane-bound and total detergent extractable protein kinase C (PKC) activities were measured. Exposure to ethanol (100 mm) resulted in an increase in PKC activity, with membrane-associated PKC activity increasing with respect to cytosolic activity at 5 min of exposure. Higher concentrations of ethanol up to 200 mm were associated with increases in total detergent extractable PKC activity. Ethanol was the most potent of a series of straight chain alcohols studied for their effects on detergent-extractable PKC activity.
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PMID:Ethanol exposure increases total protein kinase C activity in human lymphocytes. 848 78

The effects of ethanol on intracellular free Ca(2+) concentration, [Ca](i), were studied in cultured rat hippocampal neurons using fluo-3 and confocal microscopy. Ethanol application transiently elevAted [Ca](i) due to Ca(2+)-induced Ca(2+) release from internal stores since the effect was observed also in solutions containing zero Ca(2+) or 0.3 mM La(3+) and restoration of external Ca(2+) content led to secondary response in presence of ethanol. The sites of highest [Ca]i increases correlated well with those obtained after Ca(2+) release from caffeine-and IP3-sensitive internal stores. After single ethanol exposure the caffeine-evoked [Ca](i) transients were potentiated whereas Ca(2+) release induced by IP(3)-mobilizing agonists was suppressed. Similar effects were observed by activation of protein kinase C (PKC) by phorbol esters which also occluded ethanol actions. Ethanol increased fluorescence of Rim-1, a PKC indicator dye. The data obtained are consistent with ethanol activation of PKC whereby Ca(2+) release via ryanodine receptors is potentiated and IP(3) receptors are down-modulated. Since the effects of both ethanol and phorbol esters were mimicked by cytochalasins B and D, PKC-induced cytoskeleton phosphorylation and its subsequent rearrangements can be responsible for observed effects.
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PMID:Ethanol actions on the mechanisms of Ca2+ mobilization in rat hippocampal cells are mediated by protein kinase C. 886 6

Ethanol is a potent inhibitor of the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in various neuronal preparations. In primary cultures of cerebellar granule cells, ethanol was suggested to interact with the glycine co-agonist site of the receptor by a mechanism involving protein kinase C. In the present study, the interaction of ethanol with various sites on the NMDA receptor was examined in primary cultures of cerebral cortical cells from embryonic rats. NMDA receptor function was determined by measuring increases in intracellular Ca2+ with fura-2 fluorescence. Ethanol inhibited the function of the NMDA receptor in cerebral cortical cells, but in contrast to the results in cerebellar granule cells, phorbol ester treatment did not inhibit the NMDA response, and ethanol did not alter the effect of glycine on NMDA receptor function. Ethanol also did not affect inhibition of the NMDA response by Mg2+ or dizocilpine. The results support the hypothesis that the mechanism of ethanol inhibition of NMDA receptor function can vary in neurons from different brain regions.
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PMID:Mechanism of ethanol inhibition of NMDA receptor function in primary cultures of cerebral cortical cells. 886 71

The role of cytosolic phospholipase A2 (cPLA2), phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D (PLD) in the bradykinin (BK)-stimulated release of arachidonic acid (AA) was examined in Madin-Darby canine kidney (MDCK) cells. Release of AA, phosphorylcholine, choline, and phosphatidic acid (PA) or the transphosphatidylation product, phosphatidylethanol, was detected after 1 min of BK stimulation. A role for PC-PLC was confirmed with D609, which reduced BK-stimulated AA by 70%. Ethanol (EtOH), which blunts PA formation, diminished BK-stimulated AA release by 50%. Together, D609 and EtOH inhibited this release almost completely. Evidence indicated that diacylglycerol and PA can enhance PLA2 activity when added to cytosol extracts. The enzyme responsible for AA release was characterized as cPLA2, since PLA2 activity assayed in cell extracts was largely inhibited by an antibody to this enzyme. The membrane fraction PLA2 activity increased significantly in BK-stimulated cells. We conclude that BK signaling in MDCK cells is mediated by the lipid products of PC-PLC and PLD, increasing cPLA2 activity, possibly by causing perturbations in the bilayer structure of its substrate, by a direct effect on the enzyme or by activation of protein kinases such as protein kinase C.
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PMID:Role of PLA2, PLC, and PLD in bradykinin-induced release of arachidonic acid in MDCK cells. 889 11


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