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)

1. The synthesis of nitric oxide (NO) by immune-stimulated murine phagocytic cells (J774) and the modulation of this synthesis by tricyclodecan-9-yl-xanthogenate (D609), a specific inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), was investigated. D609 dose-dependently suppressed production of NO, as measured by the release of nitrite and nitrate, in response to lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) in intact cultured cells with an IC50 of approximately 20 micrograms ml-1. D609 at 40 micrograms ml-1 completely abrogated immune-stimulated nitrite production. 2. The inhibitory effects of D609 on nitrite production were time-dependent and restricted to the first 18 h post-stimulation. D609 did not inhibit nitrite production in the cytosol of immune-stimulated phagocytes. 3. These findings indicate that the xanthogenate, D609, is a potent inhibitor of the induction of NO-synthase activity in immune-stimulated phagocytes. Furthermore, since D609 has been demonstrated to inhibit PC-PLC specifically, our findings suggest that the activation of this enzyme by LPS and IFN-gamma is a proximal step in the signal transduction of inducible NO-synthase in phagocytic cells.
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PMID:Induction of nitric oxide synthase activity in phagocytic cells inhibited by tricyclodecan-9-yl-xanthogenate (D609). 753 78

Nitric oxide is a signaling molecule involved in events crucial to neuronal cell function, such as neurotransmitter release, gene transcription, and neurotoxicity, i.e., a number of processes in which a key role appears to be played by increases in intracellular Ca2+ concentration. In the neurosecretory/neuronal cell line PC-12, we have investigated the role of nitric oxide in the modulation of Ca2+ release from intracellular stores elicited by activation of three different receptors coupled to phosphatidyl-inositol-4,5-bisphosphate hydrolysis, i.e., the purinergic P2U, muscarinic M3, and bradykinin B2 receptors. The results obtained show that nitric oxide donors have an inhibitory effect on agonist-evoked Ca2+ release. This effect is not due to nitric oxide-induced modifications of Ca2+ storage, because the total releasable Ca2+ pool, measured as the radioactivity released by thapsigargin and ionomycin in cells loaded at equilibrium with 45Ca2+, was unchanged. In contrast, nitric oxide donors decreased agonist-evoked inositol-1,4,5-trisphosphate generation and total inositol phosphate accumulation. Similarly, nitric oxide inhibited total inositol phosphate accumulation stimulated by either aluminium fluoride or Ca2+. All of these effects were mimicked by the cGMP analogue 8-bromo-cGMP. When cells were incubated with nitric oxide synthase inhibitors, the results observed were opposite those produced by nitric oxide donors. All of the effects of nitric oxide were abolished when cells were treated with the cGMP-dependent protein kinase I inhibitor KT5823. Furthermore, KT5823 mimicked the effects of nitric oxide synthase inhibitors. We conclude that nitric oxide and Ca2+ signaling pathways are interconnected in PC-12 cells. Modulation of inositol phosphate generation and Ca2+ release by nitric oxide appears to be exerted primarily at the level of phospholipase C functioning and to be mediated by the activation of cGMP-dependent protein kinase I.
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PMID:Nitric oxide modulation of agonist-evoked intracellular Ca2+ release in neurosecretory PC-12 cells: inhibition of phospholipase C activity via cyclic GMP-dependent protein kinase I. 753 79

In this paper we show that isolated rat atria synthetized nitric oxide (NO) and its acts as intracellular messenger, increasing cGMP production that in turn modulates the muscarinic cholinergic dependent inhibition of contractility. Carbachol activating M2 muscarinic acetylcholine receptors (M2 mAchR) activated phosphoinositide turnover, stimulated nitric oxide synthase and increased production of NO. Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guanylate cyclase activities, shifted to the right the dose-response curve of carbachol upon contractility. Moreover, sodium nitroprusside and 8-bromo cGMP, induced negative inotropic effect. These results suggest that carbachol activating M2 mAchR exerts inotropic negative effect associated to an increase production of NO. The mechanism appears to occur secondarily to stimulation of phosphoinositide turnover via phospholipase C activation. This in turn, triggers cascade reactions leading to the production of NO, that contribute to the inotropic negative action of low concentrations of carbachol.
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PMID:Negative inotropic effect of carbachol on rat atria mediated by nitric oxide. 754 28

In porcine coronary artery endothelium-dependent relaxation to bradykinin is in part attributed to a chemically unidentified factor, termed endothelium-derived hyperpolarizing factor (EDHF). We hypothesize that arachidonic acid, acting through a cyclooxygenase-independent mechanism, is responsible for EDHF production. To define the relationship between EDHF production and arachidonic acid release, we investigated the role of phospholipase C in bradykinin-induced relaxation and prostaglandin I2 production (an index of arachidonic acid release) in porcine coronary artery. The phospholipase C inhibitor U73122 (1 mumol/L) abolished bradykinin-induced, nitric oxide-mediated relaxation but did not inhibit either bradykinin-induced, EDHF-mediated relaxation or prostaglandin I2 production. However, when given at a larger dose (20 mumol/L) U73122 abolished both bradykinin-induced, EDHF-mediated relaxation and prostaglandin I2 production. Similarly, the calcium-ATPase inhibitor thapsigargin, given at a dose (1 mumol/L) that abolished bradykinin-induced increases in intracellular calcium concentration in cultured porcine coronary artery endothelial cells, eliminated both bradykinin-induced. EDHF-mediated relaxation and prostaglandin I2 production. Although thapsigargin abolished bradykinin-induced prostaglandin I2 production, the basal production of prostaglandin I2 was enhanced and contraction of endothelium-intact rings was attenuated. These latter responses are most likely related to enhanced basal arachidonic acid release and associated EDHF production. These observations suggest that phospholipase C activation and increased intracellular calcium concentration are required for both bradykinin-induced arachidonic acid release and EDHF production in porcine coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relationship of arachidonic acid release to porcine coronary artery relaxation. 755 31

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in signal transduction. It was previously demonstrated that an antibody to an isozyme of PLC, PLC-delta, produces intense staining of neurofibrillary tangles (NFT), the neurites surrounding senile plaque (SP) cores and neuropil threads in the brains of patients with Alzheimer's disease (AD). Although the etiology of neuronal degeneration in AD is still to be defined, excitotoxic glutamate might be a candidate. In the present study, an anti-PLC-delta antibody was used to examine the influence of glutamate on PLC-delta immunoreactivity in cultured rat cortical neurons. Exposure to glutamate caused the death of cultured cortical neurons and exhibited increased immunostaining with the anti-PLC-delta antibody. Subtoxic doses of glutamate also increased PLC-delta immunoreactivity in a dose-dependent manner. Both glutamate-induced neuronal degeneration and the increases in PLC-delta immunoreactivity were prevented by removal of extracellular Ca2+ or the application of an N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. The glutamate-induced increase in PLC-delta immunoreactivity was also prevented by N omega-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor. These results suggest that NO formation secondary to Ca2+ influx by NMDA receptor activation leads to similar modifications of PLC-delta to those seen in AD.
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PMID:Glutamate-induced antigenic changes of phospholipase C-delta in cultured cortical neurons. 756 35

Nitric oxide stimulates endogenous ADP-ribosylation of cytosolic and membrane-bound proteins. Endogenous ADP-ribosyltransferases modify several intracellular proteins including the heterotrimeric GTP-binding proteins (G proteins). ADP-ribosylation of G proteins in vascular smooth muscle leads to increased activation of adenylate cyclase and decreased activation of phospholipase C leading to vasodilation. We hypothesize that in hypertension, chronically depressed endothelium-derived nitric oxide levels lead to decreased ADP-ribosylation of G proteins. This reduced ADP-ribosylation leads to vasoconstriction since activation of the G proteins by agonists is unopposed. Thus, disinhibition of G proteins, mediated by nitric oxide deficit, is responsible for the observed increased sensitivity to vasoconstrictor agonists in hypertension. This novel role for nitric oxide in hypertension will provide a new area of research for antihypertensive therapeutic intervention.
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PMID:Nitric oxide regulation of ADP-ribosylation of G proteins in hypertension. 760 67

Both sodium nitroprusside (SNP) and a phospholipase C inhibitor U73122, when applied to human platelets after the stimulation with thrombin (0.2 U/ml), caused dose-dependent inhibition of Ca2+ influx. The inhibition, however, was not complete for either substance and the U73122-resistant Ca2+ influx was also resistant to SNP. Two lines of evidence suggested that the SNP/U73122-resistant Ca2+ influx was due to the capacitative Ca2+ entry. First, U73122-resistant fraction of Ca2+ influx induced by thapsigargin was also resistant to SNP. Second, both U73122 and SNP failed to inhibit the Ca2+ influx induced by an acid extract from thrombin-stimulated platelets that contained the Ca2+ influx factor activity. We suggest that the capacitative Ca2+ entry in human platelets, once triggered by inositol trisphosphate-induced store-depletion, is not affected by nitric oxide.
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PMID:Capacitative Ca2+ entry in human platelets is resistant to nitric oxide. 761 23

Mastoparan is an amphiphilic tetradecapeptide derived from wasp venom which activates G-proteins. Several secondary effects have been attributed to this peptide, including activation of phospholipase and phosphatidylinositol kinase. The aim of the present study was to investigate the effects of mastoparan on vascular contractility. Rabbit aortic rings were cut and mounted on a force transducer to record isometric tension on a polygraph. The effects of mastoparan were then investigated on the contractile responses in the isolated rabbit aorta with or without endothelium. The results were summarized as follows; 1. Mastoparan caused biphasic response, a transient relaxation followed by a further contraction, in norepinephrine (NE)-precontracted ring with endothelium. These effects were not observed in the aorta in the absence of endothelium. 2. Mastoparan-induced transient relaxation was significantly inhibited by treatment with a N-omega-nitro-L-arginine or methylene blue. 3. When an inhibitor of phospholipase C, neomycin was added to the precontracted aortic ring with NE, the transient relaxation induced by mastoparan was inhibited, but sustained contraction was not inhibited. 4. When an inhibitor of phospholipase A2, quinacrine and inhibitor of the cyclooxygenase pathway, indomethacin, were added to a precontracted ring with NE, the transient relaxation induced by mastoparan was not inhibited, but sustained contraction was inhibited. 5. Mastoparan induced a contraction of the aorta either with or without endothelium. Indomethacin and nifedipine inhibited mastoparan-induced contraction. From the above results, we concluded that mastoparan acts on the endothelium and modifies the release of endothelium-derived relaxing factors such as nitric oxide and also endothelium-derived contracting factors such as metabolites of arachidonic acid.
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PMID:Effects of mastoparan on a vascular contractility in rabbit aorta. 766 Jun 77

The role of nitric oxide (NO) in the phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis and intracellular Ca2+ release responses induced by epidermal, platelet-derived, and fibroblast growth factors was investigated in three cell lines, a clone of NIH-3T3 fibroblasts overexpressing epidermal growth factor receptors and the tumoral epithelial cells A431 and KB. In all three cell types, pretreatment with NO donors decreased growth factor-induced PIP2 and Ca2+ responses, whereas pretreatment with NO synthase inhibitors increased them. The Ca2(+)-dependent PIP2 hydroysis induced by micromolar concentrations of the Ca2+ ionophore, ionomycin, was also modulated negatively and positively by NO donors and synthase inhibitors, respectively. In contrast, the Ca2+ content of the intracellular stores was unaffected by the various pretreatments employed. NO donors and synthase inhibitors induced an increase and decrease, respectively, of the intracellular cGMP formation in all three cell lines investigated. All of the effects of the NO donors were mimicked by 8-bromo-cGMP administration and abolished by pretreatment with the specific blocker of the cGMP-dependent protein kinase I, KT5823, which by itself mimicked the effects of the synthase inhibitors. Together with previous observations on G protein-coupled receptors, the present results demonstrate that PIP2 hydrolysis and Ca2+ release occur under the feedback control of NO, independently of the phospholipase C (beta, gamma, or delta type) involved and of the mechanism of activation. Such a control, which appears to be effected by the cGMP-dependent protein kinase I acting at the level of the phospholipases C themselves, might ultimately contribute to the inhibitory role of NO on growth previously observed with various cell types.
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PMID:Nitric oxide action on growth factor-elicited signals. Phosphoinositide hydrolysis and [Ca2+]i responses are negatively modulated via a cGMP-dependent protein kinase I pathway. 767 8

In this study, we hypothesized that histaminergic increases in venular permeability result from a cascade triggered by activation of phospholipase C (PLC), inducing the synthesis of nitric oxide (NO) and activating guanylate cyclase. The apparent permeability coefficient to albumin (Pa) was measured in isolated porcine coronary venules subjected to constant flow and hydrostatic and oncotic pressures. Histamine (2.5, 5, and 10 microM) transiently and progressively increased Pa. The PLC inhibitor 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate (NCDC; 100 microM) decreased baseline permeability and abolished the effect of histamine. The NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 10 microM) and the guanylate cyclase inhibitor 6-anilinoquinoline-5,8-quinone (LY 83583; 10 microM) also blocked the histamine-induced hyperpermeability. L-Arginine (3 mM) reversed the inhibition by L-NMMA. NG-monomethyl-D-arginine did not influence the effect of histamine. Furthermore, sodium nitroprusside (10 microM) augmented Pa by two- to threefold; this effect was blocked in the presence of LY 83583 but not altered in the presence of NCDC. The results suggest that histamine increases coronary venular permeability by a direct action on the venular endothelial cells through a PLC-NO synthase-guanylate cyclase-signaling cascade.
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PMID:Histamine increases venular permeability via a phospholipase C-NO synthase-guanylate cyclase cascade. 768 77


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