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)

The mode of action of E5510, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid, which has very potent anti-platelet activities, was investigated by examining its effects on the biochemical responses in the process of human platelet activation. In a whole-cell system, E5510 inhibited the increased turnover of inositol phospholipids arising from phospholipase C activation, arachidonic acid release from phospholipids by phospholipase A2, mobilization of intracellular free Ca2+, protein kinase C activation, and thromboxane A2 production. In a cell-free system, E5510 inhibited cyclooxygenase activity and cyclic AMP-dependent phosphodiesterase activity in a dose-dependent manner. An elevation of cyclic AMP in platelets was also observed at a relatively high concentration of E5510. It was suggested that receptor-mediated turnover of inositol phospholipids, intracellular Ca2+ increase, arachidonic acid release from phospholipids and protein kinase C activation might be indirectly inhibited by the increased cyclic AMP level in platelets. Thromboxane A2 production in the whole-cell system was very strongly inhibited by E5510, and the IC50 for this effect was 100 times lower than that of direct inhibition of cyclooxygenase in the cell-free system. It was concluded that although the primary mode of action of E5510 is the inhibition of the cyclooxygenase pathway of positive signal transduction in platelets, E5510 has another mode of action by increasing platelet cyclic AMP, which can act as a negative messenger in platelet signal transduction, and these multiple sites of action synergistically antagonize platelet cellular activation.
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PMID:A new anti-platelet drug, E5510, has multiple suppressive sites during receptor-mediated signal transduction in human platelets. 164 15

The present article deals with the stimulation of membrane PLA2 induced by activated protein kinase C (PKC), and the effect of a deficiency in cellular PKC activity in reducing in PLA2 activity. The mode of glucocorticoid (GC) inhibition action in regulation of PLA2 activity, by enhancement of protein dephosphorylation in general, and PLA2 in particular, is hypothesized and discussed. Indirect evidence strongly suggests that activated PKC enzyme is essential for the stimulation of membrane PLA2 activity induced by the Ca2+ ionophore A23187 and other agonists. Our hypothesis suggests that membrane-associated PKC directly phosphorylates PLA2 leading to its activation. Dephosphorylation of activated PLA2, possibly by a serine/threonine protein phosphatase reduces PLA2 activity. GC could induce membrane protein phosphatases which mediate their inhibitory action on PLA2 activity. This mode of action of GC is complementary to their effect in reducting in elevated [Ca2+]i, which is essential for full expression of PLA2 activity. Thus, GC exhibits multiple actions which specifically culminate in suppression of PLA2 and other phospholipases (PI-PLC and PLD) and generally in cellular inactivation (relaxation) and reduction of allergic and inflammatory responses.
Adv Prostaglandin Thromboxane Leukot Res 1991
PMID:A novel mechanism of glucocorticosteroid (GC) action in suppression of phospholipase A2 (PLA2) activity stimulated by Ca2+ ionophore A23187: induction of protein phosphatases. 184 70

The mechanisms whereby bacterial endotoxins stimulate arachidonic acid metabolism in macrophages are uncertain. Both protein kinase C activation and de novo protein synthesis occur in macrophages in response to endotoxin. In this study we evaluated the time course and role of protein kinase C and de novo protein synthesis in endotoxin stimulated arachidonic acid metabolism in resident rat peritoneal macrophages. Thromboxane (TX) B2 was measured as the representative arachidonic acid metabolite synthesized in response to Salmonella enteritidis endotoxin, calcium ionophore A23187, or phorbol 12-myristate 13-acetate (PMA). The effect of inhibition of protein kinase C by 1-(5-isoquinolinsulfonyl)-2-methylpiperazine dihydrochloride (H-7) and staurosporine on endotoxin- and A23187-induced TXB2 synthesis was examined. The potential roles of transcriptional and translational events in endotoxin- and A23187-stimulated TXB2 synthesis were determined by utilizing the transcriptional inhibitors camptothecin (10 microM) or actinomycin D (0.08 microM), and the translational inhibitor cycloheximide (0.1 microM). Whereas, A23187 stimulated maximal TXB2 synthesis within 15 min, endotoxin showed a more prolonged time course with a 12-fold increase in TXB2 synthesis above basal levels after 3 h (P less than 0.05). PMA induced an approx. 8-fold increase above basal TXB2 levels that was blocked by inhibition of transcription with actinomycin D. H-7 (10 microM to 50 microM) inhibited endotoxin- and A23187-stimulated eicosanoid synthesis. Staurosporine (0.2 microM) produced a selective 66% inhibition of endotoxin, but not A23187-stimulated TXB2 synthesis. Endotoxin-induced TXB2 production was significantly (P less than 0.05) inhibited by staurosporine, camptothecin, actinomycin D or cycloheximide at intervals from 30 min prior to, through 60 min after endotoxin stimulation. These studies suggest a role for protein kinase C activation and de novo protein synthesis in endotoxin signal transduction events leading to increased macrophage arachidonic acid metabolism. These intracellular events are essential in sustaining the prolonged inflammatory response to endotoxin.
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PMID:Endotoxin-induced arachidonic acid metabolism requires de novo protein synthesis and protein kinase C activation. 190 97

Thromboxane A2 (TXA2), a potent vasoconstrictor agent, is released from platelets and smooth muscle during inflammation and trauma. TXA2 may cause lingual artery (LA) contraction, leading to lingual paresthesia. The effects of U-46619, a TxA2 mimetic, on isolated rings of canine LA and mesenteric artery (MA) were examined. U-46619 (1 nmol/L to 1 mumol/L) caused a triphasic contraction of LA and MA; a rapid, phasic contraction; a slow, sustained contraction; and, upon washout of U-46619, a maintained contraction. The MA relaxed slowly, but the LA remained contracted for at least three h after washout. Decreasing extracellular calcium ion (Ca2+o) to less than 0.1 mumol/L with 2 mmol/L EGTA relaxed MA, but not LA. EGTA (4 mmol/L) partially relaxed the maintained contraction of LA. Inhibition of protein kinase C with amphotericin B or staurosporine inhibited the phasic and sustained contractions of LA, but did not affect the maintained contraction in the presence or absence of EGTA. Thus, CA2+o was required for the initial contraction of the LA by U-46619, but did not appear to be required for the maintained contraction following washout of U-46619. The data support the conclusion that following a brief exposure to U-46619, maintained contraction of LA persists by a unique mechanism that may be independent of Ca2+ and protein kinase C. Sustained LA contraction after exposure to endogenous TXA2 during inflammation and trauma may contribute to impaired lingual blood flow and orofacial tissue injury.
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PMID:The effect of thromboxane on contraction of canine mesenteric and lingual arteries. 191 77

Thromboxane A2 (TXA2) induces platelet shape change, secretion, and aggregation. Using a novel TXA2/prostaglandin endoperoxide receptor antagonist, [1r-[1 alpha(Z),2 beta,3 beta,5 alpha]]-(+)-7-[5-[[(1,1'- biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclopentyl]-4-heptenoic acid hydrochloride (GR32191), we demonstrate that these responses are mediated by at least two receptor-effector systems. GR32191 non-competitively inhibited platelet aggregation to the TXA2 mimetics, (15S)-hydroxy-11,9-(epoxymethano) prostadienoic acid (U46619) and [1S-(1 alpha,2 beta(5Z),3 alpha (1E,-3S), 4 alpha)]-7-[3-(3-hydroxy-4-(p-iodophenoxy)-1-butenyl)7- oxabicyclo[2.2.1]hept-2yl]-5-heptenoic acid by binding irreversibly to a TXA2/prostaglandin endoperoxide receptor. Dissociation of [3H]GR32191 from human platelets demonstrated two specific binding sites, one which was rapidly dissociating and a site to which binding was essentially irreversible. Stimulation by U46619 of platelets incubated with GR32191 and subsequently washed to expose the reversible binding site failed to aggregate or to secrete [3H]5-hydroxy-tryptamine; formation of inositol phosphates and activation of protein kinase C were markedly suppressed. In contrast, platelet shape change and calcium stimulation remained at 90% of control. Furthermore, stimulation of the reversible binding site with U46619 induced aggregation in the presence of ADP, demonstrating its functional importance in amplifying the response to other agonists. These data suggest that TXA2 mediates platelet activation through at least two receptor-effector systems; one linked to phospholipase C activation, resulting in platelet aggregation and secretion and a second site mediating an increase in cytosolic calcium and platelet shape change.
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PMID:The response to thromboxane A2 analogues in human platelets. Discrimination of two binding sites linked to distinct effector systems. 213 29

Monoclonal antibody P256, which is specific for glycoprotein IIb-IIIa complex, was found to induce aggregation of normal platelets in plasma. The mechanism of platelet activation induced by this monoclonal antibody was thoroughly studied. The divalent binding to the IIb-IIIa molecule was necessary for triggering aggregation since Fab' fragments did not induce aggregation as did IgG and F(ab')2 fragments; however, F(ab')2 did not induce the release as did the whole IgG. P256-induced aggregation was accompanied by release of all three granule constituents, namely dense granules, alpha-granules and lysosomes, with parallel kinetics showing half-maximum release 50 s after addition of P256. Thromboxane synthesis was initiated at the same time. Using 32P-prelabeled platelets, no variation in level of [32P]phosphatidylinositol 4,5-bisphosphate could be detected in the first minute after P256 addition, indicating no activation of the calcium-independent phospholipase C specific for polyphosphoinositol phospholipid. P256 induced a calcium mobilization as measured by Indo-1 fluorescence of about the third of that measured in the presence of a thrombin concentration giving the same intensity of aggregation. P256 induced phosphorylation of the myosin light chain p20 and of the main substrate of protein kinase C, p43. Addition of aspirin inhibited almost totally calcium mobilization and partially aggregation, release and protein phosphorylations. By contrast, in the absence of external calcium, although no aggregation could occur, the release reaction was only partially reduced. In this activation, the glycoprotein IIb-IIIa complex thus appears to play a role in modulating platelet response, not only via calcium fluxes but also in activating protein kinase C responsible for p43 phosphorylation.
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PMID:Activation of platelets induced by mAb P256 specific for glycoprotein IIb-IIIa. Possible evidence for a role for IIb-IIIa in membrane signal transduction. 236 45

Thromboxane A2 (TxA2) is a potent platelet agonist that serves as an amplifying signal after exposure of platelets to other stimulants, such as thrombin, in vitro. Exposure of platelets to the TxA2 receptor agonists U46619 and SQ 26,655 (1.4 microM) resulted in a 60-90% decrease in subsequent TxA2 receptor-stimulated aggregation, calcium release, and protein kinase C activation. The desensitization was rapid, with a half-time of 2-3 min. The sequence of events involved in TxA2 receptor desensitization involves initial uncoupling of the receptor from a guanine nucleotide binding (G) protein followed by eventual receptor down-regulation. Consistent with this hypothesis were (i) a 60-70% decrease in SQ 26,655-stimulated platelet GTPase activity, (ii) a shift to the right of the dose-response curve for U46619-stimulated release of calcium [EC50, 275 +/- 51 nM (control)] vs. 475 +/- 71 nM (desensitized); P less than 0.01], and (iii) a delayed loss of receptor sites. In summary, exposure of platelets to TxA2 receptor agonists results in rapid desensitization of the biochemical and functional responses to interaction with its receptor in human platelets. The kinetics of these events are consistent with the hypothesis that this icosanoid functions in the regulation as well as amplification of platelet activation in vivo.
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PMID:Regulation of thromboxane receptor activation in human platelets. 252 85

The mechanism by which agonists stimulate phospholipase A2 of platelets is still much of a mystery. We have presented a discussion that suggests that neither Ca2+, protein kinase C or dissociation of the inhibitory GTP-binding protein Gi is solely responsible for activating this enzyme. We cannot exclude the possibility that there may be some contribution of each pathway for some agonists, and that the contribution may change with agonist concentration or potency. These possibilities await further clarification.
Adv Prostaglandin Thromboxane Leukot Res 1989
PMID:Relationship of inositol phospholipid metabolism to phospholipase A2. 252 38

We have investigated factors affecting the activation of phospholipase C in human platelets. Prior exposure of platelets to phorbol esters that stimulated protein kinase C inhibits the activation of phospholipase C in response to a variety of receptor-directed agonists, including alpha- and gamma-thrombin and thromboxane A2 analogues. Such activation has been assayed by measurements of accumulated InsP3 (including Ins(1,4,5)P3 and Ins(1,3,4)P3) and PtdOH. Inhibition is not overcome by Ca2+ ionophores, and substances that block or mimic Na+-H+ exchange neither block nor mimic these inhibitory effects. Cyclic AMP and cyclic GMP, other agents known to inhibit phospholipase C activation, do not accumulate in platelets exposed to phorbol esters. Although a portion of the effects of phorbol ester on InsP3 accumulation may be explained by 5-phosphomonoesterase activity, it is likely that more direct effects on phospholipase C are being exerted as well, and contribute the major inhibitory route. We have examined the susceptibility of adenylyl cyclase-associated Gi and 'Gp'-activated phospholipase C to inhibitory ADP-ribosylation by pertussis toxin-derived enzyme (S1 protomer) administered to saponin-permeabilized platelets. The effects of alpha-thrombin on adenylyl cyclase can be inhibited by up to 50% by S1, at which point inhibition of phospholipase C is barely detectable. Thromboxane A2 analogues, which do not affect adenylyl cyclase (Gi), stimulate phospholipase C; this effect is not impaired by S1. We therefore propose that the inhibitory effects of phorbol esters on the activation of phospholipase C are not mediated primarily by effects on Gi.
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PMID:Regulation of platelet phospholipase C. 290 40

A calcium-sensitive, lipid-activated protein kinase is present in ovarian granulosa cells and may modulate granulosa cell function through an effect on granulosa cells prostaglandin F2 alpha biosynthesis. Phorbol-ester activation of this protein kinase elicits a dose- and time-dependent augmentation in the synthesis of PGF2 alpha by swine granulosa cells which can be inhibited by inhibitors of prostaglandin and protein synthesis. Our studies support a linkage between protein kinase C activation and prostaglandin F2 alpha synthesis by these cells.
Adv Prostaglandin Thromboxane Leukot Res 1987
PMID:A stimulatory role for the protein kinase C pathway in ovarian prostaglandin synthesis: studies with cultured swine granulosa cells. 296 Jan 56


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