Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Staphylococcus aureus alpha-toxin is a pore-forming exotoxin that probably represents a significant virulence factor in staphylococcal infections. Previous studies demonstrated that this agent stimulated arachidonate metabolism with subsequent formation of prostacyclin in endothelial cells and leukotriene B4 in granulocytes. We now examined the effect of alpha-toxin on the synthesis of platelet-activating factor (PAF) in cultured porcine pulmonary artery endothelial cells. PAF was labeled by bioincorporation of tritiated acetate and separated/quantitated using thin-layer chromatography, straight-phase-HPLC, or post-HPLC-bioassay. Alpha-toxin induced synthesis of small amounts of PAF in a time- and dose-dependent manner. The maximal amount of PAF elicited by alpha-toxin was approximately 7% of that observed after application of the ionophore A23187. Staphylococcal alpha-toxin but not the ionophore induced a rapid fall in cellular ATP-content. On kinetic grounds, the decrease in ATP-levels did not explain the differences in stimulated PAF-synthesis. Low amounts of PAF induced by the action of alpha-toxin on endothelial cells may contribute to the development of inflammatory lesions in infectious disease.
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PMID:Stimulation of PAF-synthesis in pulmonary artery endothelial cells by Staphylococcus aureus alpha-toxin. 144 May 26

The present study specifically addresses the role of protein kinase C (PKC) activation in human endothelial cell Ca2+ mobilization, a response that is functionally coupled to the production of the potent arachidonate (AA) metabolite, prostacyclin (PGI2). Phorbol 12-myristate 13-acetate (PMA), alpha-thrombin, and sodium fluoride (NaF), a direct G-protein activator, produced a rapid and time-dependent translocation of PKC from the cytosol to the membrane. Activation of PKC by brief pretreatment of human umbilical vein endothelial cell (HUVEC) monolayers with PMA resulted in the inhibition of NaF-induced inositol phosphate increases and attenuation of both alpha-thrombin- and NaF-activated increases in intracellular Ca2+ (Ca2+i). Ca2+ mobilization induced by ionophore A23187 was not affected by PKC preactivation, suggesting PKC-dependent negative feedback inhibition of phosphatidylinositol (PI)-specific phospholipase C (PLC). Agonist-stimulated AA release and PGI2 synthesis in PMA-pretreated cultured human endothelial cells, however, was potentiated, and the enhanced PGI2 synthesis produced by A23187, NaF, and alpha-thrombin was dependent upon the dose of PMA. Treatment of HUVEC monolayers with an intracellular Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid-acetoxymethylester (BAPTA-AM), dramatically reduced alpha-thrombin-, NaF-, and A23187-induced PGI2 synthesis, demonstrating the importance of Ca2+i availability in PGI2 synthesis. BAPTA pretreatment did not inhibit PMA-induced PKC activation, and BAPTA-mediated inhibition of agonist-stimulated PGI2 synthesis was partially attenuated by prior PMA pretreatment. Staurosporine, a potent PKC inhibitor, at concentrations that inhibited PKC-induced phosphorylation of histone-1, augmented both alpha-thrombin- and NaF-induced production of inositol phosphates but markedly inhibited alpha-thrombin-, NaF-, and A23187-induced PGI2 synthesis. The downregulation of PKC activity by prolonged PMA treatment (18 h) produced similar inhibition of PGI2 synthesis by these agonists (approximately 50% inhibition). These studies indicate that the integrated phospholipase A2 and PLC activities are under complex regulation by factors that include both PKC activation and [Ca2+i]. PKC exerts dual effects on prostaglandin synthesis via negative regulation of Gp-coupled PI-specific PLC and positive feedback regulation of AA release and PGI2 synthesis. PKC is thus a critical determinant in the regulation of human endothelial cell prostaglandin synthesis by both receptor-mediated and G-protein-dependent cellular activation.
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PMID:Role of protein kinase C in the regulation of prostaglandin synthesis in human endothelium. 154 Mar 95

1. The effect of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A (PP1 and PP2A), on human platelets has been investigated. 2. Okadaic acid exerts a general increase in phosphorylation of platelet proteins but did not induce aggregation or secretion of 5-hydroxytryptamine (5-HT). Okadaic acid, however, did inhibit thrombin-induced functional responses. 3. Maximally effective concentrations of prostacyclin, to elevate adenosine 3'-5'-cyclic monophosphate (cyclic AMP), or phorbol dibutyrate, to activate protein kinase C, inhibited the formation of inositol phosphates by thrombin by approximately 60%. When used in combination, prostacyclin and phorbol dibutyrate reduced the levels of inositol phosphates induced by thrombin to 11%. 4. Okadaic acid (1 microM) decreased thrombin-induced formation of inositol phosphates by approximately 55% and increased the inhibitory action of prostacyclin or phorbol dibutyrate. Okadaic acid had no further effect when prostacyclin and phorbol dibutyrate were used in combination. 5. These results suggest that protein kinases A and C act to inhibit phospholipase C by distinct mechanisms and that their action is reversed by PP1 and/or PP2A.
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PMID:Okadaic acid inhibits activation of phospholipase C in human platelets by mimicking the actions of protein kinases A and C. 162 49

Attempts were made to identify prostaglandin (PG) receptors in rat myometrium, according to the differential rank order of potencies displayed by the natural PGs and their analogues, both at the level of second messenger generation and contraction. In estrogen-treated rat myometrium, PGs [iloprost = PGI2 greater than PGE2 much greater than 16,16-dimethyl (DM)-PGE2; sulprostone = misoprostol = 0] induced adenosine 3',5'-cyclic monophosphate generation, indicating the contribution of a PGI2 receptor. The generation of inositol phosphates was stimulated by PGs (PGF2 alpha greater than PGD2 much greater than PGE2 = DM-PGE2 much greater than iloprost greater than sulprostone = misoprostol = 0), reflecting a PGF2 alpha-receptor-mediated process, which was insensitive to pertussis toxin (PTX). Contractions caused by PGF2 alpha were closely correlated to PGF2 alpha-receptor activation associated with the phospholipase C pathway. By contrast, contractions evoked by PGE2, equally mimicked by sulprostone and misoprostol, were abolished by PTX and were independent of phospholipase C activation. In the pregnant myometrium (day 21), the latter PGE-receptor-mediated mechanism also contributed to contractions caused by PGE2 (less than microM concn). Phospholipase C activation was coupled not only to PGF2 alpha but also to PGE receptors and could be correlated with contractions induced by PGF2 alpha and PGE2 greater than microM concn). All PGs tested were coupled to inhibitory G protein-mediated adenylate cyclase inhibition, displaying an equipotency that did not allow characterization of the inhibitory PG receptors.
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PMID:Diverse prostaglandin receptors activate distinct signal transduction pathways in rat myometrium. 163 81

We observed that in hypoxic myocardial cells prostacyclin and arachidonic acid release increased and that during hypoxia phospholipid degradation also occurred. In order to clarify the mechanism of phospholipid degradation, we determined the activity of phospholipases A2 and C. We found that phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were markedly decreased and that lysophosphatidylcholine and lysophosphatidylethanolamine were increased. In contrast, there was only slight phosphatidylinositol degradation and no lysophosphatidylinositol elevation was observed. These results show that phospholipase A2 was activated in hypoxic myocytes and had substrate specificity towards PC and PE. To study phospholipase C activity, membrane phospholipids were labeled with [3H]choline, [3H]inositol or [3H]ethanolamine. The release of inositol was observed, but neither choline nor ethanolamine was released. In hypoxia, myocardial-cell phospholipase C has high substrate specificity towards phosphatidylinositol. The activation of phospholipases is closely related to the intracellular Ca2+ concentration; it is though that inositol polyphosphatides may regulate intracellular Ca2+. We determined how Ca2+ influx occurs in hypoxia. beta-Adrenergic blockade and Ca2+ antagonists markedly suppressed Ca2+ influx, phospholipase A2 activity, phospholipase C activity and cell death. However, the alpha 1-adrenergic blockade was less effective in suppressing these phenomena. These results suggest that in hypoxic myocardial cells Ca2+ influx mediated by beta-adrenergic stimulation activates phospholipases A2 and C, and that phospholipid degradation and prostacyclin release then occur.
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PMID:Phospholipid metabolism and prostacyclin synthesis in hypoxic myocytes. 165 15

We demonstrated that the activities of phosphatidylinositide-specific phospholipase C, inositol 1,4,5-trisphosphate (IP3) kinase, and IP3 phosphatase were enhanced in cardiomyopathic hamster hearts (BIO 14.6 and BIO 53.58) in comparison to control hamsters (F1b). Release of both arachidonic acid and prostacyclin was markedly enhanced by norepinephrine in the cardiomyopathic hamsters. Phospholipase C in heart has high substrate specificity to phosphatidylinositol. IP3 production was markedly enhanced in the cardiomyopathic hamsters. We also determined the intracellular calcium concentration, which was higher in BIO 53.58 hamsters than in BIO 14.6 hamsters at 5-20 weeks of age. There was no significant difference in the intracellular calcium level between F1b and BIO 14.6 hamsters at 5 weeks of age. These results suggest that phosphatidylinositol turnover stimulated by norepinephrine may produce high intracellular calcium levels in both BIO 14.6 and BIO 53.58 myocytes. In addition, in BIO 53.58 hamsters, some mechanism such as the sarcoplasmic reticulum, which controls the intracellular calcium level, may deteriorate in function. We concluded from these results that a prolonged high intracellular calcium level may lead to the death of BIO 53.58 myocytes.
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PMID:Phospholipid metabolism in cardiomyopathic hamster heart cells. 165 36

Treatment of intact human umbilical vein endothelial cells with NaF results in a dose-dependent biphasic response in both prostacyclin and inositol phosphate production: the stimulation observed with 10-20 mM NaF decreases with higher concentrations. High concentrations of NaF furthermore reduce thrombin- or A23187-stimulated prostacyclin production. Direct assay of phospholipase C activity in cell homogenates shows a similar biphasic response to NaF, also after chelation of Ca2+; addition of AlCl3 shifts the inhibition toward lower NaF concentrations. Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) also causes a dose-dependent biphasic response in inositol phosphate formation in permeabilized cells and homogenates; a higher inhibitory concentration of GTP gamma S abolishes the stimulation of inositol phosphate production by low NaF concentrations. A high concentration of NaF furthermore inhibits the non-G-protein-dependent activation of phospholipase C by deoxycholate. NaF also induces a dose-dependent biphasic response in cyclic AMP formation in intact cells, indicating that the inhibition of phospholipase C at higher NaF concentrations does not result from a rise in cyclic AMP. The data are compatible with the existence of a guanine nucleotide-dependent, cyclic AMP-independent, phospholipase C-inhibitory pathway in endothelial cells.
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PMID:Guanine nucleotide-dependent inhibition of phospholipase C in human endothelial cells. 169 18

Human erythroleukemia (HEL) cells phosphorylate [3H]inositol 1,4,5-trisphosphate to inositol 1,3,4,5-tetrakisphosphate; they also contain all the enzymes to sequentially dephosphorylate [3H]inositol 1,4,5-trisphosphate and [3H]inositol 1,3,4,5-tetrakisphosphate to inositol. alpha-Thrombin, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, and sodium fluoride caused the formation of [3H]inositol phosphates in HEL cells that were previously labeled with [3H]inositol. This indicates agonist-induced activation of phospholipase C and hydrolysis of the inositol phospholipids. Pretreatment of the HEL cells with iloprost, a prostacyclin analog that increases cellular cyclic AMP levels, dramatically reduced the formation of inositol phosphates and the increase of [3H]phosphatidylinositol 4,5-bisphosphate. The inhibitory effects of iloprost were associated with the phosphorylation of a 24-kDa protein, which was detected with an antiserum obtained against the rap 1 protein. The catalytic subunit of protein kinase A inhibited formation of polyphosphoinositides during phosphorylation of the rap 1 protein in membranes. This rap 1 protein might have functional relevance in the inhibition of agonist-induced inositide metabolism.
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PMID:Effect of protein kinase A on inositide metabolism and rap 1 G-protein in human erythroleukemia cells. 169 2

Elevated eicosanoid biosynthesis characterizes certain forms of human and experimental glomerular proliferative disease. Thromboxane A2 (TxA2) and other prostaglandins (PG) act through specific receptors and mechanisms of intracellular signal transduction in human mesangial cells. We studied the actions of U-46619, a TxA2 mimetic which stimulates mesangial phospholipase C, and of the PGI2 analogue, Iloprost, a potent activator of adenylate cyclase, on proliferation of cultured human mesangial cells. When applied alone to quiescent cells, U-46619 had only weak mitogenic activity, as assessed by [3H]thymidine [( 3H]-TdR) incorporation and cell counts. On the other hand, addition of U-46619 10 minutes prior to stimulation of the cells with 1 to 17% fetal bovine serum (FBS) for 24 hours, potently and dose-dependently inhibited FBS-stimulated [3H]-TdR incorporation. Similarly, U-46619 inhibited the effects of 10 ng/ml platelet-derived growth factor (PDGF), epidermal growth factor or basic fibroblast growth factor on [3H]-TdR incorporation, by 55, 79 and 88%, respectively. The effects of U-46619 were not mimicked by another stimulus of phospholipase C, angiotensin II. Iloprost also inhibited FBS-activated proliferation. Neither eicosanoid inhibited the rise of cytosolic Ca2+ induced by FBS or PDGF. The actions of TxA2 and Iloprost in cultured cells point to multiple functional interactions between eicosanoids and growth factors in the control of mesangial cell proliferation.
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PMID:Regulation of human mesangial cell growth in culture by thromboxane A2 and prostacyclin. 169 33

Thrombin induced an increase in [Ca2+]i in mouse mastocytoma P-815 cells. This increase was markedly reduced by prior exposure to pertussis toxin (PT) but not by removal of extracellular Ca2+, suggesting that thrombin stimulates phospholipase C via a PT-sensitive GTP-binding protein. ATP also induced an increase in [Ca2+]i. This increase was insensitive to PT but completely suppressed on removal of extracellular Ca2+, suggesting that ATP stimulates Ca2+ influx in a PT-insensitive manner. Iloprost, a stable prostacyclin analogue, increased the cellular cAMP level and dose-dependently inhibited the thrombin-induced increase in [Ca2+]i, whereas the ATP-induced increase in [Ca2+]i was markedly enhanced by iloprost. Cyclic AMP analogues, dibutyryl cAMP and 8-bromo cAMP, also inhibited the increase in [Ca2+]i induced by thrombin and promoted that by ATP, indicating that the inhibitory and stimulatory effects of iloprost are mediated by cAMP. These results suggest that the prostacyclin receptor differentially regulates two distinct Ca2+ mobilizing systems via cAMP in mastocytoma cells.
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PMID:Differential regulation of thrombin- or ATP-induced mobilization of intracellular Ca2+ by prostacyclin receptor in mouse mastocytoma cells. 170 39


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