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)

The Ca2+ ionophore A23187 (0.2-5 microM) stimulates the phosphorylation of the substrates of protein kinase C (40,000 dalton protein) and myosin light chain kinase (20,000 dalton protein) in the presence or absence of cyclooxygenase inhibitors. In the presence of cyclooxygenase inhibitors or millimolar Ca2+ there is no stimulation of phospholipase C by A23187. Fingerprints of the 32P-labeled 40,000 dalton protein isolated from platelets that have been stimulated with A23187, thrombin, phorbol 12,13-dibutyrate and 1,2-didecanoylglycerol were identical. Higher concentrations of A23187 (1-5 microM) induced the loss of polyphosphoinositides through phosphomonoesterase activity.
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PMID:Ionophore A23187 stimulates phosphorylation of the 40,000 dalton protein in human platelets without phospholipase C activation. 301 50

Human platelets stimulated by epinephrine undergo enhanced turnover of phosphatidylinositol 4,5-bisphosphate, accumulate inositol trisphosphate, diacylglycerol, and phosphatidic acid, and phosphorylate a 47-kDa protein. All of these phenomena indicate stimulation of phospholipase C. These responses are blocked completely by inhibitors of alpha 2-adrenergic receptors (yohimbine), cyclooxygenase (aspirin or indomethacin), phospholipase A [2-(p-amylcinnamoyl)amino-4-chlorobenzoic acid (ONO-RS-082)], Na+/H+ exchange [ethylisopropylamiloride (EIPA)], fibrinogen binding to glycoprotein IIb/IIIa (antibody A2A9), Ca2+/Mg+ binding (EDTA), or removal of fibrinogen. Epinephrine evokes (i) an increased turnover of ester-linked arachidonic acid in aspirin treated platelets that is inhibited by ONO-RS-082, EDTA, yohimbine, or the absence of fibrinogen and (ii) a rapid cytoplasmic alkalinization that is inhibited partially by blockage of cyclooxygenase activity and completely by A2A9 or EIPA. In contrast, when incubated with subaggregatory concentrations of the prostaglandin H2/thromboxane A2 analogue [(15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic acid (U46619) and epinephrine, aspirin-treated platelets show a potentiation of phospholipase C activation that is unaffected by the above inhibitors. We propose that epinephrine, in promoting exposure of glycoprotein IIb/IIIa sites for fibrinogen binding, leads to a cytoplasmic alkalinization, which, in conjunction with local shifts in Ca2+, promotes low-level activation of phospholipase A. The resulting free arachidonic acid is converted to cyclooxygenase products, which, potentiated by epinephrine, activate phospholipase C. This further amplifies the initial stimulatory response.
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PMID:Activation of phospholipases A and C in human platelets exposed to epinephrine: role of glycoproteins IIb/IIIa and dual role of epinephrine. 302 70

Addition of leukotriene D4 (LTD4) to [3H]myo-inositol-labeled guinea pig lung induced rapid breakdown of inositol lipids. Formation of [3H]inositol trisphosphate was rapid, with a peak of 140-160% of the control level, 30 sec post-treatment. Formation of [3H]inositol bisphosphate and [3H]inositol monophosphate ([3H]IP1) was also rapid in the presence of LiCl. LTD4-induced [3H]IP1 formation was concentration dependent, stereoselective, and not inhibited by the cyclooxygenase inhibitor, indomethacin. Agonist analogs of LTD4 and leukotriene E4 also induced dose-dependent increases in the synthesis of [3H]IP1. The rank order potency of the agonist-induced [3H]IP1 formation was equivalent to those reported for LTD4 receptor binding, smooth muscle contraction, and thromboxane B2 biosynthesis. Furthermore, a specific receptor antagonist, SKF 102922, inhibited LTD4-induced [3H]IP1 formation in guinea pig lung. These studies suggest that LTD4 may interact with membrane receptor and activate a phospholipase C, which in turn induces the hydrolysis of inositol lipids. The hydrolysis products, diacylglycerol and inositol trisphosphate, can be regarded as the intracellular messengers for LTD4 receptors in guinea pig lung. This concept may explain a variety of pharmacological effects of leukotrienes in different types of target cells or tissues.
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PMID:Leukotriene-induced hydrolysis of inositol lipids in guinea pig lung: mechanism of signal transduction for leukotriene-D4 receptors. 302 24

Inositol 1,4,5-trisphosphate induces aggregation and the release of [3H]5-hydroxytryptamine from human platelets rendered permeable with saponin. This action of inositol 1,4,5-trisphosphate is associated with a significant formation of thromboxane B2, activation of phospholipase C, and phosphorylation of 20,000- and 40,000-dalton proteins, which are the substrates for myosin light chain kinase and protein kinase C, respectively. All of these responses are blocked by the cyclooxygenase inhibitors indomethacin and aspirin and the dual cyclooxygenase and lipoxygenase inhibitor 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW 755C). These data indicate that platelet activation by inositol 1,4,5-trisphosphate is initiated by the mobilization of Ca2+, which leads to phospholipase A2 activation. The thromboxanes and endoperoxides that are subsequently generated then induce activation via cell surface receptors.
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PMID:Inositol 1,4,5-trisphosphate induces aggregation and release of 5-hydroxytryptamine from saponin-permeabilized human platelets. 308 84

Previous studies have provided pharmacologic evidence that T lymphocyte function may be regulated in part by the intracellular production of various arachidonic acid (AA) metabolites in response to cellular stimulation. However, the specific AA metabolic capabilities of homogeneous T cell populations have not been clearly defined. In the present studies, we have employed an accessory cell-free T cell line, HT-2, as a model system for the examination of stimulus-induced eicosanoid biosynthesis in T lymphocytes. HT-2 cells were biosynthetically labeled with [3H]-AA and challenged briefly with various agents that stimulate the hydrolytic release of AA from cellular phospholipids. The bee venom peptide melittin stimulated a profound AA release response in the cells and the concomitant synthesis of both cyclooxygenase (PGF2 alpha, PGE2 and PGD2) and lipoxygenase (5-,12-,15-HETE and possibly 5-,12-diHETE) metabolites of AA. The formation of PGs was blocked by 5 microM indomethacin, demonstrating that this cell line contains cyclooxygenase activity functionally similar to that described in macrophages and other cell types. The high activity of melittin in this system was shown to result largely from a synergy between the peptide itself and a persistent bee venom phospholipase A2 contaminant. However, experiments with melittin freed of detectable phospholipase A2 activity by heating, and with synthetic homopolymers of (L)-lysine and (L)-arginine demonstrated that HT-2 cells contain sufficient endogenous, stimulus-responsive phospholipase A2 to provide both the cyclooxygenase and lipoxygenase pathways of AA metabolism ith substrate. In contrast, Ca++ ionophores, which are known to stimulate AA release and metabolism in certain cell types, stimulated only AA release but no detectable eicosanoid biosynthesis in HT-2 cells. Experiments with exogenous bacterial phospholipase C suggested that this cell line can also generate free AA for eicosanoid biosynthesis from membrane-derived 1,2-diacylglycerol. These results indicate that multiple intracellular pathways of AA metabolism are present HT-2 cells, and that the stimulus-induced release of AA and the production of eicosanoid second messengers may result from activation of either phospholipase A2 or phospholipase C.
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PMID:Stimulation of arachidonic acid release and eicosanoid biosynthesis in an interleukin 2-dependent T cell line. 308 27

Data indicating that the 21-kDa protein (p21) Harvey-ras gene product shares sequence homology with guanine nucleotide-binding proteins (G proteins) has stimulated research on the influence(s) of p21 on G-protein-regulated systems in vertebrate cells. Our previous work demonstrated that NIH-3T3 mouse cells expressing high levels of the cellular ras oncogene isolated from the EJ human bladder carcinoma (EJ-ras) exhibited reduced hormone-stimulated adenylate cyclase activity. We now report that in these cells another enzyme system thought to be regulated by G proteins is inhibited, namely phospholipases A2 and C. NIH-3T3 cells incubated in plasma-derived serum release significant levels of prostaglandin E2 (PGE2) as determined by radioimmunoassay when exposed to platelet-derived growth factor (PDGF) at 2 units/ml; the levels of PGE2 released from EJ-ras-transfected cells are only 3% those of controls despite a similar basal (unstimulated) release from control and EJ-ras-transfected cells. The lack of PDGF-stimulated PGE2 release from EJ-ras-transfected cells is not due to a defect in the prostaglandin cyclooxygenase enzyme, since incubation of control cells and EJ-ras-transfected cells in 0.33, 3.3, or 33 microM arachidonate resulted in identical levels of PGE2 release. The lack of PDGF-stimulated PGE2 release from EJ-ras-transfected cells also does not result from the loss of functional PDGF receptors. EJ-ras-transformed cells bind 70% as much 125I-labeled PDGF as control cells and are stimulated to incorporate [3H]thymidine and to proliferate after exposure to PDGF. Moreover, this inhibition is not likely the result of a secondary cellular effect related to the transformed phenotype, since NIH-3T3 cells transformed by v-src released PGE2 at wild-type levels after exposure to PDGF. Determination of total water-soluble inositolphospholipids and changes in the specific activities of phosphatidylcholine in control and EJ-ras-transfected cells demonstrated that PDGF-stimulated phospholipase C and A2 activities are inhibited in the EJ-ras-transfected cells.
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PMID:Loss of platelet-derived growth factor-stimulated phospholipase activity in NIH-3T3 cells expressing the EJ-ras oncogene. 309 98

The mechanism of tumour necrosis factor-mediated cytotoxicity was investigated by using various inhibitors of arachidonic acid metabolism. Phospholipase A2 inhibitors with different modes of action interfered with the cytotoxic action of TNF, whereas phospholipase C inhibitors did not. Neither cyclooxygenase nor lipoxygenase-blockers had a significant effect on TNF action. Experiments with scavengers of toxic oxygen radicals gave ambiguous results. The data obtained suggest the involvement of phospholipase A2 and arachidonic acid in the cytotoxic mechanism of TNF, but the exact role of these molecules is, however, still to be determined.
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PMID:Reduced tumour necrosis factor-induced cytotoxicity by inhibitors of the arachidonic acid metabolism. 312 40

Various pharmacological properties of a new antiplatelet aggregating agent, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid (E-5510), were examined in order to elucidate its mode of action, Firstly, the inhibitory effect on in vitro aggregation of platelets from humans and various experimental animals was studied. E-5510 inhibited human platelet aggregation induced by collagen, arachidonic acid, adenosine diphosphate (ADP), platelet activating factor (PAF) and epinephrine. Thrombin-induced platelet aggregation, which was not inhibited by acetylsalicylic acid (ASA) or the thiazole drug, 4,5-bis(4-methoxyphenyl)-2-(trifluoromethyl) thiazole, was inhibited by E-5510. E-5510 inhibited collagen-induced platelet aggregation in platelet-rich plasma (PRP) from guinea pigs, beagle dogs and monkey to the same degree as in human PRP, but its effect was weaker in rat PRP. Human platelet adhesion to a collagen-coated plastic disk and thrombin-induced adenosine triphosphate (ATP) release from human platelets were also inhibited by this compound. Next, the ex vivo anti-platelet effect of E-5510 was examined in guinea pigs and beagle dogs. E-5510 was the most potent among the tested drugs (ticlopidine, ASA, cilostazol and the thiazole drug. The anti-platelet effect of this compound appeared within 1 h and lasted more than 8 h after oral administration. The above results suggest that E-5510 may antagonize platelet activation by inhibiting phospholipase C and/or A2, which results in suppression of both phosphatidylinositol breakdown and arachidonic acid release from phospholipids, as well as by inhibiting cyclooxygenase. E-5510 exerted its anti-platelet action without affecting prostaglandin I2 production in the blood vessels. It is considered that E-5510 has a highly potent anti-platelet aggregating effect and a unique multi-site mode of action. This compound is a promising candidate as an antithrombotic drug for clinical use.
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PMID:Pharmacological properties of the novel anti-platelet aggregating agent 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid. 312 62

The human monocyte cell line, U937, can be induced to terminally differentiate into macrophage-like cells when treated with gamma-interferon. However, if these cells were treated with gamma-interferon and esculetin, an inhibitor of the lipoxygenase pathway, or BW755C, an inhibitor of both the lipoxygenase and the cyclooxygenase pathways, a marked inhibition in cellular differentiation occurred. In contrast, inhibitors of only the cyclooxygenase pathway had no effect on differentiation. These studies suggest a role for lipoxygenase products of arachidonic acid in the differentiation of the human U937 cell line. Arachidonic acid utilized in the production of eicosanoids is derived from phospholipids by the action of phospholipase A2 and phospholipase C. When U937 cells were cultured in medium supplemented with gamma-interferon, there was a striking increase in the level of phosphatidylcholine and phosphatidylethanolamine-specific phospholipase A2 activities and phosphatidylinositol-specific phospholipase C activity as compared to control cells. More ever, although there was not a significant difference in the incorporation of labeled arachidonic acid or linoleic acid into the major phospholipids of differentiated U937 cells as compared to undifferentiated control cells, there was a marked increase in the relative amount of the labeled arachidonic acid released from the differentiated cells as lipoxygenase products compared to cyclooxygenase products. These data suggest that lipoxygenase products may be essential in the differentiation process of U937 cells and that enhanced phospholipase enzyme activities that occur during differentiation help explain how arachidonic acid becomes available to form lipoxygenase products.
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PMID:The role of fatty acid metabolites in the differentiation of the human monocyte-like cell line U937. 313 4

Contractility responses of mice atria to alpha-adrenergic agonists (methoxamine and clonidine) were studied. The alpha-adrenergic agonists increased the rate of force development (dF/dt) and decreased contractile frequency. The positive inotropic effect was mediated through cardiac alpha-adrenoceptors, while the negative chronotropic effect involved parasympathetic activation. Blockers of phospholipase C inhibited both the positive inotropic and the negative chronotropic effects of the alpha-adrenergic agonists. Inhibitors of phospholipase A2 and cyclooxygenase activity attenuated the positive inotropic effect of the agonists without modifying the negative chronotropic effect.
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PMID:Dual effects of alpha-adrenoceptor agonist on contractility of mice isolated atria. 313 57


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