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 potential for tissue factor (TF) to enhance inflammation by factor VIIa-dependent induction of proinflammatory changes in macrophages was explored. Purified recombinant human factor VIIa enhanced reactive oxygen species production by human monocyte-derived macrophages expressing TF in vitro. This effect was dose- and time-dependent, ligand- and receptor-specific, and independent of other coagulation proteins. This receptor/ligand binding induced phospholipase C-dependent intracellular calcium fluxes. Transfection studies using a human monocyte-derived cell line (U937) demonstrated that an intact intracytoplasmic domain of TF is required for factor VIIa-induced intracellular calcium fluxes. The capacity of TF to enhance proinflammatory functions of rabbit peritoneal-elicited macrophages (production of reactive oxygen species and expression of major histocompatibility complex class II and cell adhesion molecules) was demonstrated in vivo by treatment with an anti-TF antibody. These data demonstrate that, in addition to its role in activation of coagulation, TF can directly augment macrophage activation. These effects are initiated by binding factor VIIa and are independent of other coagulation proteins. These studies provide the first demonstration of a direct proinflammatory role for TF acting as a cell-signaling receptor.
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PMID:Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. 1055 51

Tumor Necrosis Factor (TNF) is a cytokine that induces necrotic and apoptotic forms of cell death. The TNF-induced signalling mechanisms leading to necrosis or apoptosis are partially distinct, and are therefore likely to be regulated in a different way. The zinc finger protein A20 is a TNF-induced primary response gene that has been shown to inhibit TNF-induced apoptosis. However, its ability to inhibit the necrotic route of cell death as well as the underlying mechanism remains unknown. Here we show that stable expression of A20 or a fusion protein consisting of Green Fluorescent Protein (GFP) and A20 protects the TNF-sensitive fibroblast cell line L929 partially from TNF-induced necrotic cell death. TNF-induced necrosis has been shown to involve the activation of several phospholipases, as well as an increased production of reactive oxygen radicals. The reduced TNF-sensitivity of A20-expressing L929 cells was correlated with a decrease of TNF-induced phospholipase A2 (PLA2), phospholipase C (PLC) and phospholipase D (PLD) activation. Furthermore, production of mitochondrial reactive oxygen intermediates was retarded by overexpression of A20. These results demonstrate that A20 not only inhibits TNF-induced apoptosis but also TNF-induced necrosis, suggesting that it interferes with an early step in TNF signalling which is required for both types of cell death.
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PMID:Inhibition of tumor necrosis factor-induced necrotic cell death by the zinc finger protein A20. 1065 65

In this paper the effect of polychlorinated biphenyls (PCBs) on the production of reactive oxygen species (ROS) in rat synaptosomes is elucidated. The effect of methylmercury (MeHg) on rat synaptosomes was included as a positive control since several studies have investigated the ability of this substance to produce ROS. The exposure of the synaptosomes to the congener 2,2-dichlorobiphenyl (2, 2'-DCB; 12.5 microM) produced a linear increase in the formation of 2',7'-dichlorofluorescein (DCF) as a measure for the production of ROS. The congeners 2,2'-DCB (12.5 microM) and 3,3'-DCB (12.5 microM) stimulated, as expression of ROS production, a significant increase in DCF formation formation compared to the control. The congeners 2-chlorobiphenyl (2-CB) and 2,2',6-trichlorobiphenyl (2,2,6'-TCB) were active at 50 microM, whereas 2,2',4,4',5,5'-hexachlorobiphenyl (2,2',4,4',5,5'-HCB), 4,4'-DCB and 2,2',6,6'-tetrachlorobiphenyl (2, 2',6,6'-TeCB) were not active at this concentration. The increased formation of ROS in response to 2,2'-DCB and MeHg in the synaptosomes was dependent on extracellular Ca(2+). A phospholipase C inhibitor, U73122, was shown to significantly decrease the ROS formation induced by 2,2'-DCB, but did not reduce the ROS formation induced by MeHg. Ethanol (1%), a phospholipase D modulator, reduced the ROS formation induced by MeHg and by 2,2'-DCB by 33 and 52%, respectively. Wortmannin (25 nM), an inhibitor of phosphatidylinositol 3-kinase, completely inhibited the ROS formation induced by MeHg and 2,2'-DCB. It appears that the ROS-stimulating PCBs are the same congeners found to be neuroactive in other types of study. Phospholipase C and D and phosphatidylinositol 3-kinase seem to be involved in the intracellular signalling system that leads to ROS formation during PCB exposure.
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PMID:Effect of polychlorinated biphenyls on production of reactive oxygen species (ROS) in rat synaptosomes. 1066 91

Ballota nigra is a European plant known for its neurosedative properties. In this study, the ability of five phenylpropanoids (verbascoside, forsythoside B, arenarioside, ballotetroside, and caffeoyl malic acid) isolated from a hydroalcoholic extract, to bind to benzodiazepine, dopaminergic, and morphinic receptors was investigated. To carry out these studies, affinity tests with rat striata, entire brains and receptor rich preparations were employed. In addition, the phenolic aspect of these five phenylpropanoid esters led to investigate antioxidant activities using cell-free experiments and cellular experiments including isolated polymorphonuclear neutrophils (PMN). Effects of phenylpropanoid esters against reactive oxygen species as superoxide anion, peroxide hydrogen, hypochlorous acid and hydroxyl radical were tested. These molecules are liberated by PMN during inflammatory disorders, so that reproduction of this process in vitro stimulating PMN by chemical stimulants was undertaken. Results show that four of the five compounds are able to bind to the studied receptors. Inhibitory concentrations at 50% were determined and vary from 0.4 to 4.7 mg/ml. This may be in relation with the Ballota nigra known neurosedative activities. Results concerning antioxidant investigations evidence an ability to scavenge reactive oxygen species. Inhibitory concentrations at 50% obtained are comparable to those of known antioxidant drugs (mesna or N-acetyl cysteine). Moreover, the use of different stimuli having various pathways of action on PMN oxidative metabolism permits to establish that each phenylpropanoid ester has its own particular way of action by using proteine kinase C or phospholipase C pathways.
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PMID:Neurosedative and antioxidant activities of phenylpropanoids from ballota nigra. 1068 11

The phosphatidylcholine (PC)-preferring phospholipase C (PLC) from Bacillus cereus (PLC(Bc)) hydrolyzes various 1,2-diacyl derivatives of PC at different rates. Substrates with side chains having eight or more carbons are present in micellular form in aqueous media and are processed most rapidly. The catalytic efficiency (k(cat)/K(m)) for the hydrolyses of short-chain PCs at concentrations below their respective critical micelle concentrations also decreases as the side chains become shorter, and this loss of efficiency owes its origin to increases in K(m). In order to ascertain whether the observed increases in K(m) might arise from conformational changes in the glycerol backbone, nuclear magnetic resonance (NMR) experiments were performed in D(2)O to determine the (3)J(HH) and (3)J(CH) coupling constants along the glycerol subunit of 1, 2-dipropanoyl-sn-glycero-3-phosphocholine (K(m)=61 mM), 1, 2-dibutanoyl-sn-glycero-3-phosphocholine (K(m)=21.2 mM) and 1, 2-dihexanoyl-sn-glycero-3-phosphocholine (K(m)=2.4 mM). Using these coupling constants, the fractional populations for each rotamer about the backbone of each of substrate were calculated. Two rotamers, which were approximately equally populated, about the sn-1-sn-2 bond of each substrate were significantly preferred, and in these conformers, the oxygens on the sn-1 and sn-2 carbons of the backbone were synclinal to optimize intramolecular hydrophobic interactions between the acyl side chains. There was greater flexibility about the sn-2-sn-3 bond, and each of the three possible staggered conformations was significantly populated, although there was a slight preference for the rotamer in which the oxygen bearing the phosphate head group was synclinal to the oxygen at the sn-2 carbon and to the sn-1 carbon; in this orientation, the head group is folded back relative to the side chains. These studies demonstrate that there is no significant change in the conformation about the glycerol backbone as a function of side chain length in short-chain phospholipids. Thus, prior organization of the substrate seems an unlikely determinant of the catalytic efficiency of PLC(Bc), and other factors such as hydrophobic interactions or differential solvation/desolvation effects associated with the complexation of the substrate with PLC(Bc) may be involved.
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PMID:Solution conformations of short-chain phosphatidylcholine. Substrates of the phosphatidylcholine-preferring PLC of Bacillus cereus. 1070 24

Serotonin (5-HT) stimulates mitogenesis in rat renal mesangial cells through a G protein-coupled 5-HT(2A) receptor. We tested the hypothesis that oxidants might be involved in the signal transduction pathway linking the receptor to extracellular signal-regulated protein kinase (ERK). 5-HT rapidly increased the activity and phosphorylation of ERK. These effects were blocked by the 5-HT(2A) receptor antagonist ketanserin. The peak effect was noted at 5-10 min, and half-maximal stimulation was achieved at 10-30 nM 5-HT. Chemical inhibitor and activator studies supported the involvement of phospholipase C, protein kinase C (PKC), and reactive oxygen species (ROS, i.e., H(2)O(2) and superoxide) generated by an NAD(P)H oxidase-like enzyme in the ERK activation cascade. Mapping studies supported a location for the NAD(P)H oxidase enzyme and the ROS downstream from PKC. Our studies are most consistent with an ERK activation pathway as follows: 5-HT(2A) receptor --> G(q) protein --> phospholipase C --> diacylglycerol --> classical PKC --> NAD(P)H oxidase --> superoxide --> superoxide dismutase --> H(2)O(2) --> mitogen-activated extracellular signal-regulated kinase --> ERK. These studies demonstrate a role for the 5-HT(2A) receptor in rapid, potent, and efficacious activation of ERK in rat renal mesangial cells. They support a role for oxidants in conveying the stimulatory signal from 5-HT, because 1) chemical antioxidants attenuate the 5-HT signal, 2) oxidants and 5-HT selectively activate ERK to a similar degree, 3) 5-HT produces superoxide and H(2)O(2) in these cells, and 4) a specific enzyme [NAD(P)H oxidase] has been implicated as the source of the ROS, which react selectively downstream of classical PKC.
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PMID:5-HT(2A) receptors stimulate mitogen-activated protein kinase via H(2)O(2) generation in rat renal mesangial cells. 1075 Dec 27

Alzheimer's disease cybrid cells produced by replacing endogenous mitochondria in human neuroblastoma SH-SY5Y cells with platelet mitochondria from subjects with Alzheimer's disease have higher levels of reactive oxygen species than do cybrid cells with mitochondria from control subjects. These cells were used to test if this chronic mild increase in reactive oxygen species affects muscarinic receptor-coupled signaling activities. Basal and carbachol-stimulated phosphoinositide hydrolysis were higher, and there was less inhibition by glutathione depletion, in Alzheimer's disease than control cybrid cells. Elevated phosphoinositide hydrolysis in Alzheimer's disease cybrid cells also was evident upon direct activation of G-proteins (Gq/11) linked to phosphoinositide signaling or of phospholipase C, but immunoblot analyses revealed equivalent levels of Gq/11 and phospholipase C in both cell lines. These results indicate that there is up-regulation of phosphoinositide signaling in Alzheimer's disease cybrid cells in association with chronic mild oxidative stress, although treatment of cells with H(2)O(2) to induce greater acute oxidative stress caused decreases in carbachol-stimulated phosphoinositide hydrolysis that were similar in Alzheimer's disease and control cybrid cells. In contrast to phosphoinositide hydrolysis, carbachol-stimulated AP-1 DNA binding activity was lower in Alzheimer's disease than control cybrid cells, and this deficit was associated with deficient protein kinase C-mediated activation of AP-1. Overall, these results demonstrate that chronically elevated reactive oxygen species in Alzheimer's disease cybrid cells are associated with a more robust phosphoinositide signaling system, but lower signaling to activation of AP-1. These alterations may represent adaptations to exposure to oxidants, which precede more widespread deficits in signaling associated with more severe oxidative stress.
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PMID:Alterations in muscarinic receptor-coupled phosphoinositide hydrolysis and AP-1 activation in Alzheimer's disease cybrid cells. 1079 46

Expression of SH2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), a hematopoietic cell-specific adapter protein, is required to couple Syk family tyrosine kinase activation to downstream mediators such as phospholipase C (PLC)-gamma following TCR, platelet collagen receptor and mast cell Fc epsilon R stimulation. In addition to T cells, mast cells and platelets, SLP-76 is expressed in monocytes and macrophages. To determine the role of SLP-76 in Fc gamma R-stimulated signaling pathways in macrophages, we examined cultured bone marrow-derived macrophages (BMM) from SLP-76(-/-) and wild-type mice. In this study, we show that Fc gamma R cross-linking rapidly induces tyrosine phosphorylation of SLP-76 in wild-type BMM. Surprisingly, however, BMM from SLP-76(-/-) mice activate ERK2 and phosphorylate PLC-gamma 2 following Fc gamma R ligation. Furthermore, SLP-76(-/-) BMM display normal Fc gamma R-dependent phagocytic function and reactive oxygen intermediate production. SLP-76(-/-) and SLP-76(+/+) BMM secrete comparable levels of IL-12 in response to lipopolysaccharide and IFN-gamma. To examine macrophage function in vivo, SLP-76(-/-) mice were challenged i.v. with Listeria monocytogenes. SLP-76(-/-) mice survive and efficiently contain the acute phase of infection similar to wild-type mice but exhibit a stable chronic infection attributed to the lack of mature T cells. These data show that, although SLP-76 is required to couple Syk family PTK activity to downstream mediators and effector functions in Fc gamma R-induced pathways in some cell types, activation of Fc gamma R-dependent pathways occurs independently of SLP-76 in BM
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PMID:In vitro and in vivo macrophage function can occur independently of SLP-76. 1083 16

Although reactive oxygen species (ROS) are conventionally viewed as toxic by-products of cellular metabolism, a growing body of evidence suggests that they may act as signaling molecules. We have studied the effects of hydrogen peroxide (H(2)O(2))-induced oxidative stress on phospholipid signaling in cultured rat cortical astrocytes. H(2)O(2) stimulated the formation of phosphatidic acid and the accumulation of phosphatidylbutanol, a product of the phospholipase D (PLD)-catalyzed transphosphatidylation reaction. The effect of exogenous H(2)O(2) on the PLD response was mimicked by menadione-induced production of endogenous H(2)O(2). Oxidative stress also elicited inositol phosphate accumulation resulting from phosphoinositide phospholipase C (PLC) activation. The PLD response to H(2)O(2) was totally suppressed by chelation of both extracellular and cytosolic Ca(2+) with EGTA and BAPTA/AM, respectively. Furthermore, H(2)O(2)-induced PLD stimulation was completely abolished by the protein kinase C (PKC) inhibitors bisindolylmaleimide and chelerythrine and by PKC down-regulation. Activation of PLD by H(2)O(2) was also inhibited by the protein-tyrosine kinase inhibitor genistein. Finally, H(2)O(2) also stimulated both PLC and PLD in rat brain cortical slices. These results show for the first time that oxidative stress elicits phospholipid breakdown by both PLC and PLD in rat cultured astrocytes and brain slices.
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PMID:Effects of oxidative stress on phospholipid signaling in rat cultured astrocytes and brain slices. 1089 56

Phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P2) is the substrate for phosphoinositide-phospholipase C (PLC) and is required for the function of several cardiac cell plasma membrane (sarcolemma, SL) proteins. PtdIns 4,5-P2 is synthesized in the SL membrane by coordinated and successive actions of PtdIns 4-kinase and PtdIns 4-phosphate 5-kinase. These kinases and the generation of PtdIns 4,5-P2 may be a factor in the cardiac dysfunction during pathophysiological conditions of oxidative stress. Therefore, we examined the effects of different reactive oxygen species (ROS) on the kinases' activities and subsequent generation of PtdIns 4,5-P2. Exposure to the xanthine-xanthine oxidase-ROS generating system significantly reduced both SL kinase activities. Superoxide dismutase did not prevent this inhibition; however, catalase significantly prevented the xanthine-xanthine oxidase induced inhibition. Treatment of SL with hydrogen peroxide (H2O2) resulted in inhibition of both the kinases, which was prevented by catalase and dithiothreitol (DTT). Hypochlorous acid also inhibited both the kinases, which was prevented by DTT. Deferoxamine (an iron chelator) and mannitol (an *OH scavenger) did not modify the H2O2-induced depression of the kinases, eliminating any role of *OH. Furthermore, the IC50 of H2O2 on PtdIns 4-kinase and PtdIns 4-P 5-kinase was 27 and 81 microM, respectively. In addition, inclusion of reduced glutathione in the assay of the kinases in the absence of H2O2 did not affect the activities of the kinases; however, oxidized glutathione induced a significant depression. Also, a significant decline of the PtdIns 4-kinase and PtdIns 4-P 5-kinase activities due to changing of the redox ratio was observed. Thiol modifiers (N-ethylmaleimide, methyl methanethiosulfonate, or p-chloromercuriphenylsulfonic acid) were detected to depress the kinases' activities, which were substantially prevented by DTT. The results suggest that functionally critical thiol groups may be associated with PtdIns 4-kinase and PtdIns 4-P 5-kinase and that changes of their redox state by ROS can impair their activities, which may be an important factor in the oxidant-induced cardiac dysfunction.
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PMID:Oxidants depress the synthesis of phosphatidylinositol 4,5-bisphosphate in heart sarcolemma. 1105 Oct 96


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