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)

We provide evidence that the mechanism for arachidonate release from stimulated human platelets involves two enzymes: a phosphatidylinositol-specific phospholipase C (EC 3.1.4.10) and a diglyceride lipase. After incubation of platelets with thrombin for 15 seconds, 1.2 nmol of 1-stearoyl-2-arachidonoyl diglyceride per 10(9) platelets, was isolated. Arachidonate was released from this substrate by the action of diglyceride lipase located in the particulate fraction of platelets. The enzyme has a pH optimum of 7.0, is stimulated by calcium ions and reduced glutathione, and liberates 31 nmol of fatty acid per min per mg of platelet particulate protein. The diglyceride lipase has sufficient activity to account for the 5-10 nmol of arachidonate released per 10(9) platelets upon thrombin stimulation. That only arachidonate is released upon thrombin stimulation may be explained by the fact that the diglyceride substrate in platelets contains only arachidonate in the 2 position. The lipase activity found in platelet membranes can also hydrolyze the 1-position fatty acid. Stearate is not released when intact platelets are stimulated with thrombin, and the fate of this fatty acid remains to be elucidated.
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PMID:Diglyceride lipase: a pathway for arachidonate release from human platelets. 29 Sep 99

The cardiovascular effects of bradykinin require additional vasoactive mediators for a fully balanced response. This includes arachidonic acid (eicosatetraenoic acid) and its metabolites, the eicosanoids (prostaglandins, leukotrienes, thromboxanes, and others). Eicosanoid generation by bradykinin is started by binding of the peptide to specific B2 receptors at the plasma membrane. This initiates G-protein coupled stimulation of phospholipase C, IP3-induced increases in cytosolic Ca2+, and stimulation of protein kinase C. Arachidonic acid is liberated from membrane phospholipids primarily via Ca(2+)-induced stimulation of phospholipase A2 and converted into tissue-specific eicosanoids by enzymes in the vicinity. In vascular tissue, most of the available arachidonic acid is converted into vasodilator prostaglandins, i.e., prostacyclin (PGI2) and prostaglandin E2 (PGE2). These prostaglandins are involved in vasodilator actions of the kinins. There is also some evidence for generation of vasoconstrictor eicosanoids, such as thromboxane A2, under certain conditions. The biological significance of kinin-related prostaglandin formation becomes apparent after inhibition of kinin breakdown by ACE inhibitors. These compounds prevent generation of vasoconstrictor angiotensin II and stimulate endothelial eicosanoid formation via local kinin accumulation. There is evidence suggesting that kinin-induced prostaglandin generation contributes to anti-ischemic, inotropic, and blood pressure-lowering effects of the compounds. This also includes inhibition of polymorphonuclear leukocyte (PMN) accumulation in injured myocardial tissue, which is antagonized by PGI2-related pathways, stimulated by ACE inhibition and/or bradykinin.
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PMID:Role of prostaglandins in the cardiovascular effects of bradykinin and angiotensin-converting enzyme inhibitors. 128 33

The immediate reaction products of PLA2-mediated hydrolysis of phospholipids were tested for their ability to induce Ca2+ mobilization from internal stores in permeabilized ob/ob mouse pancreatic islets. Lysophospholipids and unsaturated fatty acids increased the free Ca2+ concentration in the incubation medium of permeabilized ob/ob mouse pancreatic islets. The potency of the lysophospholipids decreased in the following order: lysophosphatidylcholine = lysophosphatidylglycerol much greater than lysophosphatidylinositol greater than lysophosphatidylserine much greater than lysophosphatidylethanolamine. Arachidonic acid and palmitoleic acid had a potency comparable to lysophosphatidylinositol, while palmitic acid was ineffective. The Ca(2+)-mobilizing effect of inositol-1,4,5-trisphosphate (IP3) in permeabilized islet cells was additive to the lysophospholipid effect, indicating different sites of action. Both Ca(2+)-mobilizing effects were counteracted by the polyamine spermine, while the presence of Mg2+ shifted the Ca2+ concentrations to higher levels. Since not only an activation of a phospholipase C but also an activation of a phospholipase A2 with subsequent generation of lysophospholipids and free fatty acids is reported to occur in glucose-induced insulin secretion, the interaction of the phospholipase C reaction product IP3 with a lysophospholipid or an unsaturated fatty acid may affect the extent and duration of the rise in the free cytoplasmic Ca2+ concentration responsible for initiation of insulin secretion.
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PMID:Effect of lysophospholipids, arachidonic acid and other fatty acids on regulation of Ca2+ transport in permeabilized pancreatic islets. 158 37

Arachidonic acid may be an important mediator of insulin secretion since (1) glucose activates phospholipase A2 thus increasing endogenous unesterified levels of arachidonic acid, (2) arachidonic acid mobilizes Ca2+ from the islet endoplasmic reticulum and (3) arachidonic acid has been proposed to regulate voltage-dependent Ca2+ channels in the beta-cell. We have used the phospholipase A2 inhibitor, (p-amylcinnamoyl)anthranilic acid (ACA), to determine whether phospholipase A2 activation is required for glucose-induced insulin secretion. ACA inhibited in a dose-dependent manner glucose-induced insulin secretion, as well as glyceraldehyde and alpha-ketoisocaproic acid-induced insulin secretion. ACA also totally abolished glucose-induced arachidonate accumulation but did not affect phospholipase C suggesting that it was specific for phospholipase A2. Furthermore, ACA did not inhibit glucose oxidation. These observations suggest that glucose-induced arachidonate increase is essential for insulin secretion.
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PMID:Inhibition of phospholipase A2 and insulin secretion in pancreatic islets. 161 40

Arachidonic acid mobilization in platelets activated by low concentrations (less than or equal to 1.6 micrograms/ml) of TP 82, a monoclonal antibody against CD9, appears to consist of two distinct phases. In the first phase, limited arachidonic acid release occurs concomitantly with a shape change induced by TP 82. This appears to be dependent upon phospholipase A2 activation, since it is well preserved in the presence of aspirin, which completely blocked both intracellular Ca2+ elevation and phosphatidic acid formation which would indicate phospholipase C activation. The Na+ Exchange was also found to participate in the first phase of arachidonic acid mobilization, since extracellular Na+ depletion and ethylisopropylamiloride, a specific inhibitor of the Na+/H+ exchanger, effectively blocked this limited mobilization of arachidonic acid. The second, much larger, phase of arachidonic acid mobilization occurs with the beginning of platelet aggregation. A limited amount of thromboxane A2 formed during the first phase of arachidonic acid release plays an important role in induction of the massive arachidonic mobilization in the second phase. Factors, as yet unidentified, also appear to work synergistically with thromboxane A2 to induce the full picture of arachidonic acid mobilization.
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PMID:Two-step mobilization of arachidonic acid in platelet activation induced by low concentrations of TP 82, a monoclonal antibody against CD9 antigen. 164 50

Previous studies from this and other laboratories have shown that angiotensin II (AII) induces [Ca2+]i transients in proximal tubular epithelium independent of phospholipase C. AII also stimulates formation of 5,6-epoxyeicosatrienoic acid (5,6-EET) from arachidonic acid by a cytochrome P450 epoxygenase and decreases Na+ transport in the same concentration range. Because 5,6-EET mimics AII with regard to Na+ transport, it effects on calcium mobilization were evaluated. [Ca2+]i was measured by video microscopy with the fluorescent indicator fura-2 employing cultured rabbit proximal tubule. AII-induced [Ca2+]i transients were enhanced by arachidonic acid and attenuated by ketoconazole, an inhibitor of cytochrome P450 epoxygenases. Arachidonic acid also elicited a [Ca2+]i transient that was attenuated by ketoconazole. 5,6-EET augmented [Ca2+]i similar to that seen with AII, but was unaffected by ketoconazole. By contrast, the other regioisomers (8,9-, 11,12-, and 14,15-EET) were much less potent. [Ca2+]i transients resulted from influx through verapamil- and nifedipine-sensitive channels. These results suggest a novel mechanism for AII-induced Ca mobilization in proximal tubule involving cytochrome P450-dependent arachidonic acid metabolism and Ca influx through voltage-sensitive channels.
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PMID:An epoxygenase metabolite of arachidonic acid mediates angiotensin II-induced rises in cytosolic calcium in rabbit proximal tubule epithelial cells. 165 Jul 93

Arachidonic acid (AA)- or thromboxane A2/prostaglandin H2 (TXA2/PGH2) analog (STA2 and U-46619)-induced aggregations yielded a bell-shaped dose-response curve. The inhibitory mechanism by high concentrations of the agonists was examined. STA2 elevated cAMP level of platelet in a dose-dependent manner. And the aggregation was affected by metabolic inhibitors of cAMP. AA also rised cAMP level, and the rise was suppressed by indomethacin. These results indicate that the reduction of aggregation by high dose of the agonists is through cAMP elevation. The cAMP elevation was not suppressed by ruling out phospholipase C effects by chelation of cytoplasmic Ca2+ and inhibition of protein kinase C (PKC). These results suggest that the cAMP elevation is not due to activation of phospholipase C-linked TXA2/PGH2 receptor. 13-APA, an antagonist of TXA2/PGH2 receptor, suppressed the cAMP elevation, although ONO-3708, another antagonist, had no effect. As to be expected from this result, inhibitory effect of 13-APA on high STA2 level-induced aggregation was weaker than that of ONO-3708. The antagonists did not inhibit PGE1- or PGD2-induced cAMP elevation. These findings suggest that platelet has adenylate cyclase-linked TXA2/PGH2 receptor.
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PMID:Elevation of platelet cyclic AMP level by thromboxane A2/prostaglandin H2 receptor agonists. 166 27

The present experiments were performed to determine pathways responsible for arachidonic acid release stimulated by cholecystokinin (CCK) and phorbol ester, 4 beta-phorbol 12-myristate 13-acetate (PMA), and the roles of pathways in the secretory response in dispersed acini from guinea pig pancreas. Both CCK-octapeptide (CCK-OP) and PMA increased intracellular arachidonic acid. To determine the source of released arachidonic acid, we measured the effects of PMA and CCK-OP on cellular 1,2-diacylglycerol and lysophosphatidylcholine (LPC) and of diglyceride lipase inhibitor RHC 80267 on [3H]arachidonic acid release. Both PMA and CCK-OP increased 1,2-diacylglycerol and LPC. RHC 80267 had no effect on LPC but inhibited the increase in [3H]arachidonic acid release with a concentration of CCK-OP that was maximal for enzyme secretion. The increase in [3H]arachidonic acid release with PMA or a supramaximal concentration of CCK-OP was not inhibited by RHC 80267. In parallel fashion, RHC 80267 inhibited amylase release caused by maximally effective concentrations of CCK-OP but not that caused by PMA or by supramaximally effective concentrations of CCK-OP. Arachidonic acid stimulated amylase release. Exogenous addition of phospholipase A2 caused increases in [3H]arachidonic acid release, LPC formation, and amylase release. The results indicate that there are at least two pathways responsible for the increase in free cellular arachidonic acid stimulated by pancreatic agonists. One is sequential action of phospholipase C and diglyceride lipase on phosphatidylinositol. The other is a phospholipase A action on phosphatidylcholine. The results also suggest a stimulatory role for both pathways in the secretory response.
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PMID:Dual pathways for agonist-stimulated arachidonic acid release in pancreatic acini: roles in secretion. 170 48

Mastoparan, a basic tetradecapeptide isolated from wasp venom, is a novel mitogen for Swiss 3T3 cells. This peptide induced DNA synthesis in synergy with insulin in a concentration-dependent manner; half-maximum and maximum responses were achieved at 14 and 17 microM, respectively. Mastoparan also stimulated DNA synthesis in the presence of other growth promoting factors including bombesin, insulin-like growth factor-1, and platelet-derived growth factor. The synergistic mitogenic stimulation by mastoparan can be dissociated from activation of phospholipase C. Mastoparan did not stimulate phosphoinositide breakdown, Ca2+ mobilization or protein kinase C-mediated phosphorylation of a major cellular substrate or transmodulation of the epidermal growth factor receptor. In contrast, mastoparan stimulated arachidonic acid release, prostaglandin E2 production, and enhanced cAMP accumulation in the presence of forskolin. These responses were inhibited by prior treatment with pertussis toxin. Hence, mastoparan stimulates arachidonic acid release via a pertussis toxin-sensitive G protein in Swiss 3T3 cells. Arachidonic acid, like mastoparan, stimulated DNA synthesis in the presence of insulin. The ability of mastoparan to stimulate mitogenesis was reduced by pertussis toxin treatment. These results demonstrate, for the first time, that mastoparan stimulates reinitiation of DNA synthesis in Swiss 3T3 cells and indicate that this peptide may be a useful probe to elucidate signal transduction mechanisms in mitogenesis.
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PMID:Mastoparan, a novel mitogen for Swiss 3T3 cells, stimulates pertussis toxin-sensitive arachidonic acid release without inositol phosphate accumulation. 170 71

Primary cultures of endometrial glands and stromal cells were labelled with [14C]-arachidonic acid for 4 h before exposure to either the calcium ionophore, A23187 (which activates phospholipase A2 (PLA2) by increasing intracellular calcium concentrations) or sodium fluoride (which activates a G-protein). Calcium ionophore (0.5-50 mumol/l) stimulated a dose- and time-dependent release of arachidonic acid from endometrial glands. Incubation with ionophore (10 mumol/l) for 1 h released 22% of the incorporated arachidonic acid. There was a corresponding decrease in phospholipids and no loss from triglycerides. Stromal cells were unresponsive to ionophore. Fluoride (10 mmol/l) stimulated a release of arachidonic acid from stromal cells and endometrial glands (6.5% of the total arachidonic acid incorporated). In stromal cells, arachidonic acid was released from triglycerides in Day-1 cultures and from phospholipids in Day-2 cultures. In both Day-1 and Day-2 cultures of endometrial glands, arachidonic acid was released from phospholipids, but not from triglycerides. Among the phospholipids, phosphatidylcholine was always the major source of arachidonic acid. Arachidonic acid release from endometrial glands and stromal cells may be mediated by activation of PLA2 (or phospholipase C) via a G-protein, but in glands calcium ionophore may have a direct effect on PLA2. The response to calcium ionophore may reflect the differences in calcium requirements of the two endometrial PLA2 isoenzymes.
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PMID:Release of arachidonic acid from human endometrial cells in culture mediated by calcium ionophore (A23187) or fluoride. 178 65


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