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)

Since carvedilol has been claimed to possess antioxidative effects, this drug might affect functional responses, including nitric oxide (NO) generation, of polymorphonuclear neutrophils (PMN) and macrophages. When we assessed the effects of carvedilol on PMN responses in vitro, we observed that carvedilol dose dependently modulated generation of superoxide ions by NADPH oxidase when induced by the formylpeptide formyl-methionyl-leucyl-phenylalanine (fMLP) or the phorbol ester phorbol myristate acetate. This effect was not coupled to diminished phospholipase C activity. In contrast to the effect on NADPH oxidase, neither the fMLP-elicited NO generation by PMN nor the response of the murine macrophage cell line J774 to lipopolysaccharide was affected. There was no evidence from cell-free assay systems that carvedilol is a scavenger for superoxide ions or NO. Moreover, carvedilol did not affect other reactions dependent on NO, e.g. spontaneous or fMLP-stimulated PMN migration or lipoxin A(4)-, fMLP-, or A23187-induced neutrophil cytotoxicity for human umbilical vein endothelial cells. Thus, these effects point to the possibility that carvedilol modulates the NADPH oxidase of PMN but leaves the nitric oxide synthase of phagocytes intact.
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PMID:No effect of carvedilol on nitric oxide generation in phagocytes but modulation of production of superoxide ions. 1069 66

The properties of the enzymatic system responsible for generating H2O2/O2- in the lignifying xylem of Zinnia elegans were studied using the starch/KI method for monitoring H2O2 production and the nitroblue tetrazolium method for monitoring superoxide anion production. The results showed that H2O2/O2- production by lignifying xylem tissues was insensitive to inhibitors of peroxidase and poly(di)amine oxidases. However, H2O2/O2 production in the xylem of Z. elegans was sensitive to the inhibitors of phagocytic plasma membrane NADPH oxidase, pyridine, imidazole, quinacrine and diphenylene iodonium. The sensitivity of H2O2/O2- production to the respective inhibitors of calmodulin (R-24571), phospholipase C (neomycin sulfate), and protein kinase (staurosporine), and its reversion by an inhibitor of protein phosphatases (cantharidin); pointed to the analogies existing between the mechanism of H2O2/O2- production in the lignifying xylem of Z. elegans and the oxidative burst observed during the hypersensitive plant cell response. These results suggest the existence of a metabolic cascade involving calmodulin, IP3 and protein phosphorylation in the activation of the enzymatic system responsible for H2O2/O2- production in the lignifying xylem of Z. elegans.
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PMID:Some properties of the H2O2/O2- generating system from the lignifying xylem of Zinnia elegans. 1069 53

Autophosphorylation of the platelet-derived growth factor (PDGF) receptor triggers intracellular signaling cascades as a result of recruitment of Src homology 2 domain-containing enzymes, including phosphatidylinositol 3-kinase (PI3K), the GTPase-activating protein of Ras (GAP), the protein-tyrosine phosphatase SHP-2, and phospholipase C-gamma1 (PLC-gamma1), to specific phosphotyrosine residues. The roles of these various effectors in PDGF-induced generation of H(2)O(2) have now been investigated in HepG2 cells expressing various PDGF receptor mutants. These mutants included a kinase-deficient receptor and receptors in which various combinations of the tyrosine residues required for the binding of PI3K (Tyr(740) and Tyr(751)), GAP (Tyr(771)), SHP-2 (Tyr(1009)), or PLC-gamma1 (Tyr(1021)) were mutated to Phe. PDGF failed to increase H(2)O(2) production in cells expressing either the kinase-deficient mutant or a receptor in which the two Tyr residues required for the binding of PI3K were replaced by Phe. In contrast, PDGF-induced H(2)O(2) production in cells expressing a receptor in which the binding sites for GAP, SHP-2, and PLC-gamma1 were all mutated was slightly greater than that in cells expressing the wild-type receptor. Only the PI3K binding site was alone sufficient for PDGF-induced H(2)O(2) production. The effect of PDGF on H(2)O(2) generation was blocked by the PI3K inhibitors LY294002 and wortmannin or by overexpression of a dominant negative mutant of Rac1. These results suggest that a product of PI3K is required for PDGF-induced production of H(2)O(2) in nonphagocytic cells, and that Rac1 mediates signaling between the PI3K product and the putative NADPH oxidase.
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PMID:Platelet-derived growth factor-induced H(2)O(2) production requires the activation of phosphatidylinositol 3-kinase. 1074 45

Synapsins are synaptic vesicle-associated phosphoproteins involved in synapse formation and regulation of neurotransmitter release. Recently, synapsin I has been found to bind the Src homology 3 (SH3) domains of Grb2 and c-Src. In this work we have analyzed the interactions between synapsins and an array of SH3 domains belonging to proteins involved in signal transduction, cytoskeleton assembly, or endocytosis. The binding of synapsin I was specific for a subset of SH3 domains. The highest binding was observed with SH3 domains of c-Src, phospholipase C-gamma, p85 subunit of phosphatidylinositol 3-kinase, full-length and NH(2)-terminal Grb2, whereas binding was moderate with the SH3 domains of amphiphysins I/II, Crk, alpha-spectrin, and NADPH oxidase factor p47(phox) and negligible with the SH3 domains of p21(ras) GTPase-activating protein and COOH-terminal Grb2. Distinct sites in the proline-rich COOH-terminal region of synapsin I were found to be involved in binding to the various SH3 domains. Synapsin II also interacted with SH3 domains with a partly distinct binding pattern. Phosphorylation of synapsin I in the COOH-terminal region by Ca(2+)/calmodulin-dependent protein kinase II or mitogen-activated protein kinase modulated the binding to the SH3 domains of amphiphysins I/II, Crk, and alpha-spectrin without affecting the high affinity interactions. The SH3-mediated interaction of synapsin I with amphiphysins affected the ability of synapsin I to interact with actin and synaptic vesicles, and pools of synapsin I and amphiphysin I were shown to associate in isolated nerve terminals. The ability to bind multiple SH3 domains further implicates the synapsins in signal transduction and protein-protein interactions at the nerve terminal level.
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PMID:Specificity of the binding of synapsin I to Src homology 3 domains. 1089 72

This study investigates the effects of aliphatic (n-heptane, n-nonane), naphtenic (methylcyclohexane, 1,2,4-trimethylcyclohexane (TMCH)), and aromatic (methylbenzene, 1,2,4-trimethylbenzene (TMB)) hydrocarbons on respiratory burst in human granulocytes. The free radical formation was measured as 2,7-dichlorofluorescein diacetate-amplified (DCF) fluorescence, by electron paramagnetic resonance (EPR) spectroscopy and by hydroxylation of 4-hydroxybenzoate. The chemotactic peptide N-formyl-met-leu-phe (fMLP) and phorbol 12-myristate 13-acetate (PMA), a diacylglycerol analogue, were included as positive controls. DCF fluorescence was elevated in a concentration-dependent manner by C9 hydrocarbons. The C7 hydrocarbons did not stimulate respiratory burst in the concentration range examined. The naphtenic hydrocarbon TMCH showed the strongest effect on respiratory burst and was therefore selected for mechanistic studies of this free radical formation. In the absence of extracellular Ca(2+), fluorescence in response to TMCH and fMLP was reduced by 77 and 90%, respectively. Preincubation of the granulocytes with the protein kinase C inhibitor bisindolylmaleimide reduced the DCF fluorescence stimulated with TMCH, fMLP, and PMA by 82, 56, and 90%, respectively. The phospholipase C inhibitor U73122 lowered the TMCH- and fMLP-activated DCF fluorescence by 87 and 76%. In addition, the TMCH- and fMLP-induced DCF fluorescence, after the preincubation with the phospholipase D modulator n-butanol, was lowered by 83 and 52%, respectively. The importance of protein kinase C, phospholipase C, and phospholipase D for elevation of respiratory burst was also demonstrated by the EPR experiments using the spin trap 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO). Preincubation with the NADPH oxidase inhibitor diphenyleneiodonium and diethyldithiocarbamate, which inhibits superoxide dismutase, led to an almost complete reduction of DCF fluorescence in response to TMCH, fMLP, and PMA. Preincubation with diethyldithiocarbamate led to the elevation of superoxide adducts of DEPMPO. The hydrocarbons stimulated formation of mainly the superoxide (O(*-)(2)) adduct of DEPMPO (DEPMPO-OOH) but also small amounts of the hydroxyl adduct ((*)OH) (DEPMPO-OH). Using 4-hydroxybenzoate as a hydroxyl radical trap confirmed formation of (*)OH after stimulation with the hydrocarbons. In conclusion, our findings indicate that TMCH-activated respiratory burst is dependent on the Ca(2+)-dependent phospholipase C, phospholipase D, and protein kinase C prior to activation of the NADPH oxidase.
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PMID:The effects of aliphatic (n-nonane), naphtenic (1,2, 4-trimethylcyclohexane), and aromatic (1,2,4-trimethylbenzene) hydrocarbons on respiratory burst in human neutrophil granulocytes. 1098 13

We examined the mechanism of action of lysophosphatidylcholine (lyso-PC), which is suggested to be involved in the pathogenesis of atherosclerosis and inflamatory disorders, and its interaction with well-known vasoactive compounds such as hydrogen peroxide (H2O2), thromboxane A2 (TX-A2), serotonin (5-HT), angiotensin II (Ang-II), endothelin-1 (ET-1), or urotensin II (U-II) on VSMC proliferation. Growth-arrested rabbit VSMCs were incubated with given concentrations of lyso-PC with H202, TX-A2, 5-HT, Ang-II, ET-1, or U-II. [3H]Thymidine incorporation into DNA was measured as an index of VSMC proliferation. Lyso-PC induced a maximal effect on [3H]thymidine incorporation at a concentration of 15 microM (156%), and its effect was significantly inhibited by the phospholipase C inhibitor U73122 (10 microM), the intracellular antioxidant NAC (400 microM), and the NADPH oxidase inhibitor diphenylene iodonium (1 microM), but not by the MAPK kinase inhibitor (10 microM). H2O2, TX-A2, 5-HT, Ang-II, ET-1, or U-II also stimulated [3H]thymidine incorporation in a dose-dependent manner. A non-mitogenic concentration of lyso-PC (5 microM) significantly potentiated the effect of low concentrations of H2O2 (0.1 microM, 110 to 222%), TX-A2 (5 microM, 120 to 202%), 5-HT (5 microM, 182 to 259%), Ang-II (0.5 microM, 167 to 304%), ET-1 (0.01 microM, 139 to 297%), or U-II (0.025 microM, 120 to 332%) on [3H]thymidine incorporation. The results suggest that lyso-PC acts synergistically with the vasoactive compounds H2O2, TX-A2, 5-HT, Ang-II, ET-1, or U-II in inducing VSMC proliferation, which may play an important role in the progression of atherosclerosis.
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PMID:Lysophosphatidylcholine potentiates the mitogenic effect of various vasoactive compounds on rabbit aortic smooth muscle cells. 1222 16

Reactive oxygen species (ROS) play an important role in cell signaling pathway. Previously, we found that silica induced immediate ROS generation and sequential cellular responses such as kinase activation in Rat2 cells as well as an increase of intracellular calcium concentration in A549 cells. However, the detailed mechanism underlying the immediate ROS generation induced by silica in fibroblast cells remains to be elucidated. Therefore, in the present study, we investigated the mechanism of ROS generation by silica within Rat2 fibroblast cells by examining the effects of a diverse group of inhibitors for the enzymes related with signal transduction events. Inhibitors for protein tyrosine kinase (PTK), phospholipase C (PLC), protein kinase C (PKC) and calmodulin (CaM) kinase II effectively suppressed ROS generation in silica-stimulated Rat2 cells, whereas those for protein kinase A and phospholipase A(2) did not. Diphenyleneiodonium chloride (DPI), an inhibitor for NADPH oxidase was also found to be effective in inhibiting silica-induced ROS generation. These results suggest that PTK, PLC, PKC, CaM kinase II, and NADPH oxidase are all involved in signal transduction pathways for ROS generation in silica-stimulated Rat2 cells.
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PMID:Mechanism of silica-induced ROS generation in Rat2 fibroblast cells. 1227 Jun 76

In order to investigate the underlying mechanism of HCl in oesophagitis, the inflammatory response to HCl was observed in RBL-2H3 mast cells. Rat basophilic leukemia (RBL-2H3) cells were used to measure histamine release, arachidonic acid (AA) release, reactive oxygen species (ROS) and peroxynitrite generation induced by HCl. Exogenous HCl increased the level of histamine release and ROS generation in a dose dependent manner, whereas it decreased the spontaneous release of [3H] AA and the spontaneous production of peroxynitrite. Mepacrine (10 microM), oleyloxyethyl phosphorylcholine (10 microM) and bromoenol lactone (10 microM) did not affect both the level of histamine release and ROS generation induced by HCl. U73122 (1 microM), a specific phospholipase C (PLC) inhibitor did not have any influence on level of histamine release and ROS generation. Propranolol (200 microM), a phospholipase D (PLD) inhibitor, and neomycin (1 mM), a nonspecific PLC and PLD inhibitor, significantly inhibited both histamine release and ROS generation. Diphenyleneiodonium (10 microM), a NADPH oxidase inhibitor, and tiron (5 mM), an intracellular ROS scavenger significantly inhibited the HCl-induced histamine release and ROS generation. These findings suggest that the inflammatory responses to HCl is related to histamine release and ROS generation, and that the ROS generation by HCl may be involved in histamine release via the PLD pathway in RBL-2H3 cells.
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PMID:Histamine release by hydrochloric acid is mediated via reactive oxygen species generation and phospholipase D in RBL-2H3 mast cells. 1243 4

Exposure to atherogenic levels of low-density lipoprotein (LDL) causes elevated reactive oxygen species (ROS) production by human endothelial cells (ECs). NADPH oxidase is thought to be the main source of ROS generated by LDL-activated ECs. The mechanism by which this lipoprotein activates endothelial NADPH oxidase is incompletely understood. To gain further insight into the signaling pathway, the authors have examined the effects of inhibitors to various signal transducing enzymes, including the G(i)-protein coupled receptor (pertussis toxin), Src tyrosine kinase (PP1), phospholipase C-gamma (U73122), phosphatidylinositol 3-kinase (LY294002), p42/p44 mitogen-activated protein kinase (MAPK) kinase (PD98059), p38 MAPK (SB203580), protein kinase C (Ro 318220, GF 109203X, Go 6976), and cytosolic phospholipase A(2) (AACOCF3), on the ROS-producing capacity ECs activated by LDL. Exposure of cultured ECs to LDL (0.45 mg protein/mL) stimulated ROS formation, as measured using a 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate assay. This effect was partially inhibited by Ro 318220, GF 109203X, U73122, and SB203580, and blocked or nearly completely inhibited by PP1, pertussis toxin, LY294002, PD98059, and AACOCF3. Only a partial, minor inhibition occurred with the protein kinase C inhibitor, Go 6976. These results are most consistent with LDL activating endothelial NADPH oxidase, predominantly through a signaling pathway that leads to cytosolic phospholipase A(2) activation.
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PMID:Endothelial NADPH oxidase: mechanism of activation by low-density lipoprotein. 1474 44

Generation of active oxidative species induced by shear stress in suspension cultures of Taxus cuspidata was investigated in a Couette-type shear reactor. It was found that T. cuspidata cells respond to a shear rate of 95 s(-)(1) with oxidative bursts. Their triphasic characteristics in 6 h were similar in both intracellular H(2)O(2) production and extracellular O(2)(-)( )(*) production. Additionally, inhibition studies with diphenylene iodonium and azide suggested that the key enzyme responsible for oxidative bursts under the shear rate of 95 s(-)(1) is primarily NADPH oxidase and the contribution of peroxidase for oxidative bursts was less. Investigation of the relationship between active oxidative species and defense responses induced by the shear stress indicated that the O(2)(-)( )(*) burst may account for the change of membrane permeability, and the H(2)O(2) burst plays an important role in inducing secondary metabolites such as the activation of phenylalanine ammonia lyase enzyme and phenolic accumulation. Furthermore, oxidative bursts elicited by the shear rate of 95 s(-)(1) were suppressed by treatment with suramin, nifedipine, and neomycin prior to the shear stress treatment, suggesting that G-protein, Ca(2+) channel, and phospholipase C are involved in the signal pathway for oxidative bursts induced by the shear stress. A model is proposed to explain the oxidative burst in cultured T. cuspidata cells challenged with the shear stress.
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PMID:Oxidative burst in suspension culture of Taxus cuspidata induced by a laminar shear stress in short-term. 1505 96


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