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)

Phorbol esters such as phorbol 12, 13-dibutyrate (PdBu; 40 to 200 nmol/L) or 12-O-tetradecanoyl phorbol 13-acetate (20 to 80 nmol/L) added to aspirinized platelet-rich plasma (PRP) 5 to 15 seconds prior to various platelet stimuli (epinephrine, ADP, prostaglandin endoperoxide analog U44069, collagen, PAF, or vasopressin) potentiate the rate and extent of aggregation and ATP secretion induced by those agonists. Platelet aggregation, but not secretion, is potentiated at low concentrations of agonists; platelet secretion is potentiated at higher concentrations of the platelet stimuli. Potentiation of platelet responses was also observed when the preincubation time with PdBu was extended to 12 minutes and also occurred in washed platelets. The potentiating effect of phorbol esters is not mediated by formation of arachidonate metabolites or by released ADP. The sensitizing effect of PdBu on platelet aggregation induced by epinephrine is unique, since in contrast to the other platelet stimuli it is also found at maximal concentrations of epinephrine and does not diminish with prolonged preincubation of platelets with PdBu. Activation of protein kinase C ranges from 20% to 80% over control after 1 to 10 minutes of platelet pretreatment with PdBu but dramatically increases after subsequent addition of a stimulus such as vasopressin. In contrast, agonist-induced myosin light chain phosphorylation is reduced after platelet pretreatment with PdBu. The results indicate that protein kinase C activation enhances platelet aggregation and dense granule secretion triggered by physiologic stimuli, although it desensitizes agonist-induced myosin light chain phosphorylation.
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PMID:Phorbol esters sensitize platelets to activation by physiological agonists. 366 38

Phorbol ester PMA and low concentrations of calcium ionophore A-23187, which given separately have minimal effect in stimulating thromboxane synthesis in human platelets, showed marked synergism when given simultaneously. A similar synergism can be also demonstrated between thrombin or collagen and low concentrations of A-23187 but not of PMA. Simultaneous addition of thrombin and PMA results in less synthesis of thromboxane than that of thrombin alone. These studies suggest that protein kinase C activation by agonists may not only induce but also regulate thromboxane synthesis in human platelets.
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PMID:Synergistic stimulation of thromboxane biosynthesis by calcium ionophore and phorbol ester or thrombin in human platelets. 392 8

Thrombin and trypsin induce serotonin release and aggregation in human platelets. Both proteases induce activation of phospholipase C as reflected by formation of inositol phosphates and phosphorylation of the resultant 1,2-diacylglycerol to phosphatidic acid. Also, thrombin and trypsin activate protein kinase C and myosin light chain kinase as indicated, respectively, by phosphorylation of the 40,000 and 20,000 dalton proteins. Leupeptin, a known inhibitor of serine proteases, blocks all the observed responses of human platelets to trypsin and thrombin. Leupeptin does not inhibit serotonin release and aggregation induced by other platelet stimuli such as collagen, platelet-activating factor, ionophore A23187, and arachidonic acid. The implication of a proteolytic-mediated pathway in the transmembrane signalling involved in platelet activation is discussed.
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PMID:Leupeptin selectively inhibits human platelet responses induced by thrombin and trypsin; a role for proteolytic activation of phospholipase C. 405 85

The secretion evoked in human platelets by physiological agonists is an energy-requiring process that depends on the metabolic ATP pool. Diacylglycerol, phorbol ester and collagen evoke a secretory response, which is not associated with an increase of cell Ca2+ levels, and is attributed to activation of protein kinase C [(1983) Nature 305, 317-319]. The secretion evoked by these agonists decreased along with cytoplasmic ATP depletion in the same way that the thrombin-induced secretion did. The secretory response was restored by raising again the cytoplasmic ATP levels. These results support the idea that the secretory response takes place by the physiological ATP-dependent mechanisms rather than by membrane perturbations in these instances.
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PMID:Ca2+-independent secretion is dependent on cytoplasmic ATP in human platelets. 405 12

Dihomogammalinolenic acid (2.5-20 microM) added to suspensions of washed human platelets induces platelet shape change and the formation of 1,2-diacylglycerol and phosphatidic acid, indicating the activation of phospholipase C. It also stimulates the phosphorylation of a 40 kDa protein, indicating the activation of protein kinase C. Dihomogammalinolenic acid is converted mainly to 12-hydroxyheptadecadienoic acid and to a smaller extent to prostaglandin E1 and thromboxane B1. Small quantities of the lipoxygenase product 12-hydroxyeicosatrienoic acid are also observed. Indomethacin, by blocking platelet cyclooxygenase, prevents the activation of phospholipase C, protein kinase C, and platelet shape change induced by dihomogammalinolenic acid. Compound UK 38485, a specific thromboxane synthetase inhibitor, does not block platelet activation induced by dihomogammalinolenic acid. The results indicate that endoperoxides derived from dihomogammalinolenic acid, such as prostaglandin G1 or prostaglandin H1, may be responsible for the stimulation of phospholipase C and protein kinase C, and for the induction of platelet shape change. Eicosapentaenoic acid does not activate platelets and is poorly metabolized by platelet cyclooxygenase and lipoxygenase. Eicosapentaenoic acid is a better inhibitor of platelet activation induced by various agonists in washed platelets than dihomogammalinolenic acid. Eicosapentaenoic acid and dihomogammalinolenic acid are, however, equally effective in inhibiting aggregation induced by collagen in platelet-rich plasma. We suggest that eicosapentaenoic acid might be a better antithrombotic agent than dihomogammalinolenic acid.
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PMID:Dihomogammalinolenic acid, but not eicosapentaenoic acid, activates washed human platelets. 608 12

Six beta-adrenoceptor antagonists (propranolol (+ and - isomers); ICI-118,551; oxprenolol; timolol; metoprolol; and practolol (+ and - isomers), chosen to represent a spectrum of physicochemical and pharmacological properties, inhibited the response of human platelets to all aggregating agents tested. For any given aggregating agent the extent of inhibition correlated with the lipid solubility of the beta-adrenoceptor antagonist and showed no relation to other properties of these compounds. Inhibition of aggregation by the beta-adrenoceptor antagonists was manifested as a parallel shift to the right in the dose-response curve. Analysis of these data according to Arunlakshana and Schild (Br. J. Pharmac. 14, 48-58 (1969] showed a dependence of the apparent pA2 on the agonist employed and gave a slope approximating unity when ADP, 9,11-epoxymethanoprostaglandin H2 (U-46619), adrenaline, 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (PAF) or arachidonate were used as agonists. Slopes significantly greater than unity, and approaching a value of 2, were obtained when this analysis was applied to data obtained using collagen in the presence or absence of aspirin, 12-O-tetradecanoylphorbol-13-acetate (TPA), or a divalent cation ionophore (A-23187) as agonists. Inhibition by (+/-) propranolol of secretion induced by collagen was manifested as a parallel shift to the right in the dose-response curve for collagen. The Schild plot of these data has a slope of unity. (+/-)-Propranolol inhibited thromboxane B2 production induced by collagen but over a similar concentration range had little effect on conversion of arachidonate to thromboxane B2. (+/-)Propranolol had no significant effect on the level of cyclic-3',5'-AMP (cAMP) in unstimulated platelets or on the increase in the level caused by addition of forskolin, but caused partial inhibition of the increase in platelet cAMP induced by prostaglandin E1. It also completely abolished inhibition by ADP of the increase in [cyclic-3',5'-AMP] induced by prostaglandin E1. These data are interpreted on the basis of a model in which interaction of propranolol with phosphatidylserine and phosphatidylinositol causes inhibition of phospholipases C and A2, inhibition of protein kinase C and alteration of membrane receptor properties as a consequence of distortion of their microenvironment.
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PMID:Beta-adrenoceptor antagonists and human platelets: relationship of effects to lipid solubility. 614 45

In human platelets stimulated by thrombin and collagen, diacylglycerol is rapidly produced from phosphatidylinositol. Concurrently, an endogenous protein having a molecular weight of about 40,000 (40K protein) is phosphorylated, and serotonin is released. These reactions are all inhibited by a prior treatment of platelets with prostaglandin E1, dibutyryl cyclic AMP, sodium nitroprusside, or with 8-bromo-cyclic GMP, which are known as potent inhibitors for platelet activation. Ca2+-activated phospholipid-dependent protein kinase (protein kinase C) preferentially phosphorylates 40K protein. As judged by fingerprint analysis, the sites in 40K protein that are phosphorylated during the platelet activation appear to be identical with those phosphorylated by protein kinase C in a purified cell-free system. 12-O-Tetradecanoylphorbol-13-acetate, which directly activates protein kinase C by substituting for diacylglycerol, stimulates 40K protein phosphorylation and release reaction without inducing diacylglycerol formation. Tetracaine, which inhibits protein kinase C by competing with phospholipid, blocks 40K protein phosphorylation and serotonin release without inhibiting the receptor-linked diacylglycerol formation. The results indicate that thrombin and collagen activate platelets in almost similar mechanisms and that protein kinase C may lie on a common pathway which leads to the release of serotonin. However, analysis with indomethacin indicates that the role of thromboxane A2 appears to be more predominant for the action of collagen, and it is suggestive that this arachidonate metabolite activates platelets in an analogous mechanism to thrombin.
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PMID:A role of calcium-activated phospholipid-dependent protein kinase in human platelet activation. Comparison of thrombin and collagen actions. 621 69

Trifluoperazine, chlorpromazine and other drugs known to inhibit calmodulin-dependent processes are also known to inhibit protein kinase C. The effect of these agents on secretion evoked by known activators of C-kinase has been studied in human platelets loaded with the fluorescent Ca indicator, quin2 and preincubated with aspirin. The secretory response stimulated by phorbol ester and exogenous diacylglycerol, at basal levels of cytoplasmic free Ca2+, [Ca2+]i, was suppressed by trifluoperazine, chlorpromazine and W-7, as was the secretion evoked by collagen that occurs without a change in [Ca2+]i. The response to thrombin, which is accompanied by elevated [Ca2+]i was barely affected. Modest elevation of [Ca2+]i by Ca ionophore was able to overcome the inhibitory effect of these drugs on the response to phorbol ester, diacylglycerol, and collagen.
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PMID:Trifluoperazine and chlorpromazine block secretion from human platelets evoked at basal cytoplasmic free calcium by activators of C-kinase. 622 39

The derivation and properties of JB6 mouse epidermal clonal cell lines are reviewed and the conclusions that can be drawn from studies with the JB6 mouse epidermal system are summarized. Promoter induced mitogenic stimulation, epidermal growth factor (EGF) receptor binding and stimulated hexose transport are apparently not required for promotion of neoplastic transformation in JB6 cells by phorbol esters and other promoters. Phorbol ester receptor binding (or protein kinase C activation) and switched-off collagen synthesis may be required but definitive proof is not available. Decreased cell surface ganglioside GT synthesis, elevated superoxide, and one or more genes that determine promotion sensitivity appear to distinguish sensitive from resistant cells and to be required for promotion of neoplastic transformation in JB6 cells. The hypothesis is proposed that GT is a target for reactive oxygen elevated by 12-O-tetradecanoylphorbol-13-acetate (TPA) exposure and that GT oxidation produces decreased GT net synthesis which in turn leads to promotion of transformation. Finally evidence is presented suggesting the involvement of at least two genes in transformation of JB6 cells by TPA, one in induction, the other in maintenance of transformation.
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PMID:Membrane and genetic events in tumor promotion: studies with promoter resistant variants of JB6 cells. 639 88

Degradation of inositides induced by phospholipase C in activated platelets leads to the formation of 1,2-diacylglycerol (1,2-DG) and its phosphorylated product, phosphatidic acid (PA). We have studied the relationship between activation of phospholipase C and the appearance of specific platelet responses, such as phosphorylation of proteins, shape change, release reaction and aggregation induced by different stimuli such as thrombin, platelet-activating factor, collagen, arachidonic acid (AA) and dihomogamma linolenic acid. A low degree of platelet activation induces only shape change which is associated with partial activation of phospholipase C (formation of phosphatidic acid), and phosphorylation of both a 40K molecular weight protein (protein kinase C activation) and a 20K molecular weight protein (myosin light chain). A higher degree of platelet activation induces aggregation, release of serotonin and a higher level of phospholipase C and protein kinase C activities. Metabolism of AA occurs concomitantly to aggregation and serotonin release, but AA metabolites are not related to the shape change of human platelets. Platelet shape change and the initial activation of phospholipase C induced by thrombin or platelet-activating factor is independent of the metabolites derived from cyclo-oxygenase activity. Further activation of phospholipase C which occurs during platelet aggregation and release reaction is, however, partly dependent on cyclo-oxygenase metabolites.
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PMID:The role of phospholipase C in platelet responses. 641 9


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