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)

Guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG)-stimulated phospholipase C (PLC) activity in bovine brain coated vesicles is inhibited by glutamate agonists. In the present study we show that quisqualic acid (QA), (+/-)-trans-1-aminocyclopentane-1,3-dicarboxylate (trans-ACPD), glutamic acid and ibotenic acid inhibited p[NH]ppG-stimulated PLC by 44, 41, 36 and 25% respectively. Carbachol also produced an inhibition of p[NH]ppG-stimulated PLC by 45%. The inhibition caused by trans-ACPD and QA was dose-dependent. DL-2-Amino-3-phosphonopropionic acid and (RS)-alpha-methyl-4-carboxyphenylglycine, specific antagonists of metabotropic glutamate receptors (mGluRs), abolished these inhibitory effects. trans-ACPD inhibition of p[NH]ppG-stimulated PLC was also observed in the presence of ionotropic glutamate receptor antagonists. When carbachol and QA or trans-ACPD were combined, additive inhibitory effects were observed. Preincubation of bovine brain coated vesicles with pertussis toxin abolished the inhibitory effects of mGluR analogues and carbachol on p[NH]ppG-stimulated PLC activity. The presence of Gs alpha and pertussis toxin substrates, Gi alpha and Go alpha subunits as well as PLC beta 1 in bovine brain coated vesicles has been confirmed by immunoblot. These results support the coupling of mGluRs to a PLC in an inhibitory manner through a pertussis toxin-sensitive G-protein in bovine brain coated vesicles.
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PMID:Metabotropic glutamate receptor analogues inhibit p[NH]ppG-stimulated phospholipase C activity in bovine brain coated vesicles: involvement of a pertussis toxin-sensitive G-protein. 774 17

1. RBL-2H3 cells permeabilized with alpha-toxin responded to dinitrophenol (30-40 mol/mol)-conjugated human serum albumin, as antigen, to secrete [14C]serotonin in the micromolar range of free Ca2+. 2. Calcium ion alone did not cause substantial secretion. 3. Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) (100 microM) in combination with Ca2+ produced only negligible [14C]serotonin secretion. 4. GTP gamma S, in the presence of cytochalasin D, caused optimal secretion of [14C]serotonin in a Ca(2+)-dependent manner.
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PMID:Fc epsilon RI-stimulated Ca(2+)-dependent secretion from rat basophilic leukemia (RBL-2H3) cells permeabilized with Staphylococcal alpha-toxin: Fc epsilon RI-operated signals are not mimicked by the actions of GTP gamma S. 795 35

The purpose of this study was to determine whether the increased sensitivity of uterine resistance arteries from late pregnant (LP) rats to alpha-adrenergic stimulation is due to an alteration in the fundamental relationship between cytosolic calcium (Ca2+) and arterial lumen diameter. Uterine arcuate arteries were permeabilized with Staphylococcus aureus alpha-toxin under optimal conditions and constricted to varying degrees with discrete Ca2+ concentrations at a distending pressure of 50 mmHg. Arterial segments from nonpregnant (NP) and LP rats exhibited similar Ca2+/lumen diameter characteristics. Ca2+ (0.1 microM) produced appreciable constriction, and lumen diameter decreased steeply between 0.175 and 0.25 microM Ca2+; maximal responses were attained with 0.5 microM Ca2+. Activation of guanine nucleotide binding proteins (G proteins) with guanosine 5'-triphosphate (GTP; 1-100 microM), as reportedly occurs during alpha-adrenergic stimulation, potentiated the Ca(2+)-induced constriction by 121 and 79% in arteries from LP and NP rats, respectively. No significant differences between the two animal groups were noted. Guanosine 5'-O-(gamma-thiotriphosphate) (GTP gamma S; 0.1-10 microM), a nonhydrolyzable analogue of GTP, effected a larger potentiating effect over that maximal response caused by GTP in arteries from NP rats. Ca(2+)- and Ca2+/GTP-induced constrictions were more potently reversed by guanosine 5'-O-(beta-thiodiphosphate) (GDP beta S)., a competitive inhibitor of GTP, in arteries from NP rats. These data suggest that pregnancy-induced increases in sensitivity to alpha-adrenergic stimulation may be related to altered G protein cycling rates, such that G proteins in smooth muscle cells in arcuate arteries from NP rats are more susceptible to deactivation. Alternatively, consistent with the model of G protein-mediated inhibition of myosin light chain phosphatase, myosin light chain phosphatase activity may be enhanced in uterine vascular smooth muscle from NP rats relative to that from LP rats.
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PMID:Modulation of uterine resistance artery lumen diameter by calcium and G protein activation during pregnancy. 809

The ability of epidermal growth factor, insulin or guanosine thiotriphosphate to induce the release of two glycosyl-phosphatidylinositol-linked proteins from isolated human placental syncytiotrophoblast plasma membrane vesicles was investigated. Epidermal growth factor induced the ATP-dependent release of a fraction of syncytiotrophoblast plasma membrane placental alkaline phosphatase, whereas no release was detected following insulin treatment. This effect of epidermal growth factor was apparent at 30 min but not at 5 min. Guanosine thiotriphosphate stimulated the release of a small amount of syncytiotrophoblast plasma membrane placental alkaline phosphatase and appeared to have an additive effect when applied together with epidermal growth factor. Guanosine thiodiphosphate did not induce phosphatase release, but partially inhibited the epidermal growth factor response. 28.7% of syncytiotrophoblast plasma membrane 5'-nucleotidase was solubilized using glycosyl-phosphatidylinositol-specific phospholipase C. However, unlike placental alkaline phosphatase, no detectable release of 5'-nucleotidase was observed following treatment of syncytiotrophoblast plasma membrane vesicles with epidermal growth factor or guanosine thiotriphosphate. These results indicate (i) the presence of at least two placental alkaline phosphatase-releasing pathways in syncytiotrophoblast plasma membrane vesicles, and (ii) the presence of subpopulations of glycosyl-phosphatidylinositol-linked proteins sensitive to growth factor-induced release.
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PMID:Growth factor-induced release of placental alkaline phosphatase from human syncytiotrophoblast membranes. 818 14

The regulatory mechanism(s) of a phosphoinositide-specific phospholipase C, PLC-delta 1, was investigated using a clone of stably overexpressed PLC-delta 1 (PLC delta 30 cells) in Chinese hamster ovary cells. Thrombin stimulation of PLC delta 30 cells exhibited 6.5-fold increase in total inositol phosphates (InsP), which was significantly higher than that in the vector-transfected (V1) cells (2.0-fold). AIF-4 increased InsP accumulation in both V1 and PLC delta 30 cells, and pertussis toxin partially blocked InsP accumulation in thrombin-stimulated PLC delta 30 cells. Guanosine thiotriphosphate (GTP gamma S) markedly potentiated thrombin-stimulated InsP generation in permeabilized PLC delta 30 cells compared with V1 cells, suggesting possible involvement of a G-protein (s) in the activation of PLC-delta 1. In PLC delta 30 cells, ionomycin-induced significant InsP generation and thrombin-stimulated InsP generation were completely inhibited by addition of EGTA. Furthermore, the stimulatory effects of thrombin plus GTP gamma S in PLC delta 30 cells were more sensitive to change in free calcium concentration than in V1 cells. Suppression by 12-O-tetradecanoylphorbol 13-acetate of thrombin-stimulated InsP accumulation was not affected by increasing Ca2+ concentration. These results indicate that thrombin-induced PLC-delta 1 activation is regulated via both G-protein(s) and calcium.
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PMID:Thrombin-mediated phosphoinositide hydrolysis in Chinese hamster ovary cells overexpressing phospholipase C-delta 1. 819 39

Members of the Gq alpha subfamily of heterotrimeric guanine nucleotide-binding proteins (G proteins) activate phospholipase C (PLC). The complementary DNAs (cDNAs) for the G protein alpha subunits Gq alpha and G11 alpha were expressed in insect (Sf9) cells using recombinant baculovirus. Active, nonaggregated, and membrane-associated protein was generated only when the alpha subunit cDNA was expressed together with cDNAs encoding G protein beta and gamma subunits. Recombinant alpha subunits (rGq alpha and rG11 alpha) were purified by three-step procedures, as was a PLC-activating alpha subunit(s) endogenous to Sf9 cells. Guanosine 5'-3-(thio)triphosphate (GTP gamma S) activated rGq alpha and rG11 alpha with an apparent K0.5 of 30 microM; similarly high concentrations of the nucleotide were required to observe [35S]GTP gamma S binding to rGq alpha. Activated rGq alpha and rG11 alpha each stimulated all three isoforms of purified PLC-beta with the rank order of potency PLC-beta 1 = PLC-beta 3 > or = PLC-beta 2; both alpha subunits also stimulated PLC-beta 1 and PLC-beta 3 to a much greater extent (10-fold) than they did PLC-beta 2. In contrast, activated rGq alpha and rG11 alpha failed to stimulate either PLC-delta 1 or PLC-gamma 1. Recombinant Gi alpha 1, Gi alpha 2, Gi alpha 3, Go alpha (A), Gs alpha, and Gz alpha all failed to stimulate any of the isoforms of PLC. The apparent affinities of rGq alpha and rG11 alpha for PLC-beta 1 and their capacities to activate the enzyme were similar to values observed for purified brain Gq alpha/11 alpha. Purified brain beta gamma subunits also stimulated the three isoforms of PLC-beta. The capacities of rGq alpha and rG11 alpha to activate PLC-beta 1 and PLC-beta 3 greatly exceeded those of beta gamma, whereas Gq alpha, G11 alpha and beta gamma were roughly equiefficacious with PLC-beta 2; the alpha subunits were more potent than beta gamma in all cases. The effects of alpha and beta gamma together were nonadditive for both PLC-beta 1 and PLC-beta 2. These results demonstrate that Gq alpha and G11 alpha specifically and selectively stimulate beta isoforms of PLC and confirm the idea that these members of the Gq alpha subfamily of G proteins are physiological regulators of this signaling pathway.
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PMID:Purification from Sf9 cells and characterization of recombinant Gq alpha and G11 alpha. Activation of purified phospholipase C isozymes by G alpha subunits. 831 96

Treatment of cultured bovine carotid artery endothelial cells with 10(-7) M plasmin increased arachidonate release coupled with the increase in prostacyclin production. The stimulatory effect of plasmin on arachidonate release could be divided into the early and late phases according to its calcium dependency and pertussis toxin sensitivity. The early phase of plasmin-induced arachidonate release was a calcium-dependent and pertussis toxin-sensitive response, which was observed within 20 min after plasmin treatment. The late phase was a calcium-independent and pertussis toxin-insensitive response, which was induced gradually from 20 to 60 min. Induction of the early phase of plasmin's effect required both the lysine binding and catalytic sites in plasmin molecule because it was inhibited either by the binding antagonist tranexamic acid or by the serine protease inhibitor aprotinin. Guanosine 5'-O-(2-thiotriphosphate) potentiated the effect of plasmin in permeabilized or nonpermeabilized cells, indicating that the early phase effect was mediated by a pertussis toxin-sensitive guanosine 5'-triphosphate (GTP)-binding protein. The late phase of plasmin's effect was due to the catalytic activity because it was inhibited by aprotinin but not by tranexamic acid. Microplasmin structurally having the catalytic sites induced a similar late phase effect. Plasmin did not elicit the metabolism of phosphatidyl polyphosphoinositides. These studies demonstrate that the activation of phospholipase A2, which results in arachidonate release, in the early phase of plasmin's effect is a receptor-mediation via GTP-binding protein that is not coupled through phospholipase C activation.
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PMID:Human plasmin induces a receptor-mediated arachidonate release coupled with G proteins in endothelial cells. 838 26

Phospholipase C is involved in the insulinotropic effect of carbachol (CCh) and cholecystokinin octapeptide (CCK-8). The involvement of the type of G protein was investigated in rat pancreatic islets. Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S; a nonhydrolyzable GTP analogue) increased insulin release in electrically permeabilized islets. Both CCh and CCK-8 increased the GTP gamma S effect indicative of an involvement of G proteins. Pretreatment of the islets with pertussis toxin (PT) impaired the CCh-induced insulin secretion in the presence of 3.0 mM glucose and inhibited the stimulatory CCh effect on inositol 1,4,5-trisphosphate (IP3) levels at low and high glucose. In contrast to CCh, the CCK-8 effect on both insulin release and IP3 levels of islets was not modified by a PT pretreatment at various glucose concentrations. Two types of experiments indicate the type of G protein involved: first, long-term agonistic stimulation by either CCh or CCK-8 led to a downregulation of alpha o and alpha q/11, respectively; second, introduction of specific anti-alpha o or -alpha q/11 antibodies into electrically permeabilized islets nearly completely abolished the effects of CCh and CCK-8, respectively. The data indicate that both CCh and CCK-8 act as insulinotropic agents via the phospholipase C system; in the effect of CCh the PT-sensitive alpha o and in the effect of CCK-8 the PT-insensitive alpha q/11 is involved.
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PMID:Involvement of G proteins in the effect of carbachol and cholecystokinin in rat pancreatic islets. 876 83

Imaging [Ca2+]i at high temporal resolution and measuring the properties of Ca2+ signaling in streptolysin O (SLO)-permeabilized cells were used to study the spacial organization of signaling complexes. Sequential stimulation of single cells within pancreatic acini with several Ca2+-mobilizing agonists revealed an agonist-specific pattern and propagation rate of Ca2+ waves in the same cells, with CCK8 stimulating the fastest and bombesin the slowest waves. More importantly, each agonist initiated the wave in a different region of the same cell. On the other hand, repetitive stimulation with the same agonist induced Ca2+ waves of the same pattern that were initiated from the same region of the cell. The agonist-specific Ca2+ signaling does not appear to be the result of coupling to different G proteins as infusion of an anti-Galphaq antibody into the cells through a patch pipette equally inhibited Ca2+ signaling by all agonists. Further evidence for compartmentalization of signaling complexes was developed in permeabilized cells. The time-dependent loss of Ca2+ signaling due to SLO permeabilization occurred in an agonist-specific manner in the sequence cabachol > bombesin > cholecystokinin. Signaling by all agonists could be completely restored with as low as 2 micro guanosine 5'-3-O-(thio)triphosphate (GTPgammaS). At this low concentration GTPgammaS recoupled inositol 1,4,5-trisphosphate production and Ca2+ release, rather than enhancing phospholipase C activity. Priming of Ca2+ signaling by GTPgammaS was agonist-specific. Guanosine 5'-O-(thio)diphosphate (GDPbetaS) uncoupled the ability of signaling complexes to release Ca2+ much better than stimulating inositol 1,4,5-trisphosphate production. The uncoupling of Ca2+ signaling by GDPbetaS was also agonist-specific. The combined findings of agonist-specific initiation sites of the Ca2+ wave and differential access of guanine nucleotides to signaling complexes suggest spacial compartmentalization of Ca2+ signaling complexes. Each complex must include a receptor, G protein, and phospholipase C that are coupled to a specific portion of the Ca2+ pool.
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PMID:Spacial compartmentalization of Ca2+ signaling complexes in pancreatic acini. 879 36

Exogenous sphingosine 1-phosphate (S1P) stimulated hydrogen peroxide (H2O2) generation in association with an increase in intracellular Ca2+ concentration in FRTL-5 thyroid cells. S1P also induced inositol phosphate production, reflecting activation of phospholipase C (PLC) in the cells. These three S1P-induced events were inhibited partially by pertussis toxin (PTX) and markedly by U73122, a PLC inhibitor, and were conversely potentiated by N6-(L-2-phenylisopropyl)adenosine, an A1-adenosine receptor agonist. In FRTL-5 cell membranes, S1P also activated PLC in the presence of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), but not in its absence. Guanosine 5'-O-(2-thiodiphosphate) inhibited the S1P-induced GTP gamma S-dependent activation of the enzyme. To characterize the signaling pathways, especially receptors and G proteins involved in the S1P-induced responses, cross-desensitization experiments were performed. Under the conditions where homologous desensitization occurred in S1P-, lysophosphatidic acid (LPA)-, and bradykinin-induced induction of Ca2+ mobilization, no detectable cross-desensitization of S1P and bradykinin was observed. This suggests that the primary action of S1P in its activation of the PLC-Ca2+ system was not the activation of G proteins common to S1P and bradykinin, but the activation of a putative S1P receptor. On the other hand, there was a significant cross-desensitization of S1P and LPA; however, a still significant response to S1P (50-80% of the response in the nontreated control cells) was observed depending on the lipid dose employed after a prior LPA challenge. S1P also inhibited cAMP accumulation in a PTX-sensitive manner. We conclude that S1P stimulates H2O2 generation through a PLC-Ca2+ system and also inhibits adenylyl cyclase in FRTL-5 thyroid cells. The S1P-induced responses may be mediated partly through a putative lipid receptor that is coupled to both PTX-sensitive and insensitive G proteins.
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PMID:Sphingosine 1-phosphate stimulates hydrogen peroxide generation through activation of phospholipase C-Ca2+ system in FRTL-5 thyroid cells: possible involvement of guanosine triphosphate-binding proteins in the lipid signaling. 897 7


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