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)

We have previously demonstrated that platelet-activating factor (PAF) binds specifically on cell membranes isolated from U937 cells. We now describe biological evidence showing that the effect of PAF on U937 cells is a receptor-mediated event. myo-[3H]Inositol-labeled U937 cells were used to investigate the possible role of phosphoinositide metabolism in these cells after binding of PAF. Formation of inositol phosphates (IP1, IP2, and IP3) in response to PAF was increased two- to threefold more than in vehicle control in U937 cells. The effect of PAF on endogenous protein phosphorylation was also studied by using 32PO4-labeled cells. PAF stimulates the phosphorylation of a 45-kDa protein in a time-dependent and dose-related fashion. Since the phospholipase C-generated diglyceride is an important activator of protein kinase C, the phosphorylated 45-kDa protein could be the substrate of protein kinase C. In this regard, we were able to demonstrate that phorbol ester enhances the phosphorylation of the same 45-kDa protein band. In addition, sphingosine, a protein kinase C inhibitor, inhibits the phosphorylation of the same 45-kDa protein band. Down-regulation of the protein kinase C also inhibits the 45-kDa protein phosphorylation. These results suggest that protein kinase C is involved in the PAF-U937 cell interaction.
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PMID:Activation mechanisms of platelet-activating factor in U937 cells: possible involvement of protein kinase C. 165 12

Complement receptor (CR)-mediated phagocytosis is associated with an increased accumulation of diglyceride (sn-1,2-diacylglycerol and/or 1-O-alkyl-2-acyl-glycerol) in human neutrophils. The C3bi-mediated increase in diglyceride (5-20 min) was only partially impaired when phosphoinositide-specific phospholipase C (PLC) activity was abolished by reduction of cytosolic free Ca2+. At an early time point (1 min), however, diglyceride production was barely detectable in control cells, whereas production was considerable in cells with a reduced cytosolic free Ca2+ concentration. C3bi stimulation of 32P-labeled neutrophils caused a rapid and significant breakdown of [32P]phosphatidylcholine (PC) which was not affected by inhibition of Ca(2+)-dependent phosphoinositide-specific PLC. Thus, PC hydrolysis could be involved in C3bi-induced diglyceride formation. Stimulation of cells labeled with [3H]1-O-alkyl-lyso-PC ([3H]alkyl-lyso-PC), resulted in an increased formation of [3H]1-O-alkyl-phosphatidic acid ([3H]alkyl-PA) and a later and slower formation of [3H]1-O-alkyl-diglyceride ([3H]alkyl-diglyceride); this suggests activation of phospholipase D (PLD). When these labeled cells were stimulated in the presence of 0.5% ethanol a marked accumulation of [3H]1-O-alkyl-phosphatidylethanol ([3H]alkyl-PEt) was observed in both controls and calcium-reduced cells, further strengthening the suggested involvement of PLD activity. In parallel with the sustained increase in diglyceride formation, CR-mediated phagocytosis was also associated with phosphorylation of a cellular protein kinase C substrate (MARCKS). Therefore it seems reasonable to suggest a causal relationship between C3bi-induced PLD activation, which results in diglyceride formation, and activation of protein kinase C. In electropermeabilized cells which were incapable of ingesting particles, C3bi particles were still able to activate PLD and induce formation of diglyceride. This signaling event must therefore be triggered by binding of particles to the cell and not by the engulfment process. Most importantly, introduction of the protein kinase C inhibitor peptides, PKC(19-36) and PKC(19-31), into these permeabilized cells resulted in a clear reduction of the C3bi-induced production of diglyceride, indicating that CR-mediated activation of protein kinase C directly triggers a positive feedback mechanism for additional diglyceride formation. Taken together, these data further clarify the mechanisms of CR-mediated diglyceride formation and give added support to the concept that protein kinase C plays an important role in the phagocytic process.
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PMID:Complement receptor-mediated phagocytosis is associated with accumulation of phosphatidylcholine-derived diglyceride in human neutrophils. Involvement of phospholipase D and direct evidence for a positive feedback signal of protein kinase. 173 62

The effect of adenosine, 2-chloroadenosine (CAD), and 5'-(N-ethylcarboxamido)-adenosine (NECA) on the contraction produced by phorbol 12,13-dibutyrate (PDB) was investigated in porcine coronary artery in vitro to determine whether adenosine receptor-mediated relaxation was linked to protein kinase C. Also, the coronary relaxation produced by adenosine and NECA in KCl-contracted coronary rings was investigated before and after treatment with the phospholipase C inhibitor neomycin to examine a possible link between phospholipase C and adenosine receptor-mediated relaxation. Ring segments of coronary artery were suspended in organ baths for measurement of isometric force. PDB (10 nM-1 microM) caused concentration-dependent contraction, and this response was significantly attenuated by pretreatment with the protein kinase C inhibitor staurosporine (200 nM) but not 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (10 microM). Treatment of rings with either adenosine, CAD, or NECA (100 microM) significantly attenuated the PDB-induced contraction, whereas treatment with either sodium nitroprusside (SNP; 1 microM) or isoproterenol (Isop; 1 microM) did not affect the contraction produced by PDB. The attenuation of the PDB-induced contraction by adenosine and its analogues was blocked by prior treatment of the coronary rings with 8-phenyltheophylline (10 microM). In a separate series of experiments, pretreatment of rings with the phospholipase C inhibitor neomycin (1 mM) resulted in a significant attenuation of the relaxing response to both adenosine and NECA while having no significant effect on the relaxation-response to SNP or Isop. These results provide indirect evidence that adenosine receptor-mediated relaxation in porcine coronary artery may be linked to modulation of protein kinase C and phospholipase C.
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PMID:Protein kinase C and phospholipase C in adenosine receptor-mediated relaxation in coronary artery. 175 May 39

These experiments examined the mechanism by which phenylephrine enhances beta-adrenoceptor-stimulated cyclic AMP formation in rat hypothalamic and preoptic area slices. To this end we manipulated phospholipase C. phospholipase A2, and protein kinase C activity in slices and assessed the effects of these manipulations on phenylephrine augmentation of isoproterenol-stimulated cyclic AMP generation. Since previous work indicated that estrogen enhances the alpha 1-component of cyclic AMP formation, we examined slices from both gonadectomized and estrogen-treated animals. The alpha 1-antagonist prazosin eliminated phenylephrine augmentation of the beta-response, suggesting that alpha 1-adrenergic receptors mediate the potentiation of cyclic AMP formation. Inhibition of protein kinase C by H7 attenuated the alpha 1-augmentation of beta-stimulated cyclic AMP formation. Staurosporine, a more potent protein kinase C inhibitor, completely abolished the alpha 1-augmenting response. In addition, phenylephrine potentiation of the isoproterenol response was not observed if protein kinase C was first stimulated directly with a synthetic diacylglycerol (1-oleoyl-2-acetyl-sn-glycerol) or phorbol ester (phorbol 12,13-dibutyrate). Neomycin, an inhibitor of phospholipase C, decreased alpha 1-receptor enhancement of beta-stimulated cyclic AMP formation, whereas quinacrine, an inhibitor of phospholipase A2, did not. The data suggest that the postreceptor mechanism involved in alpha 1-adrenergic receptor potentiation of cyclic AMP generation in hypothalamic and preoptic area slices includes activation of phospholipase C and protein kinase C.
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PMID:Protein kinase C and phospholipase C mediate alpha 1- and beta-adrenoceptor intercommunication in rat hypothalamic slices. 184 2

The effect of ethanol on receptor-mediated phospholipase C-linked signal transduction processes was investigated in isolated rat hepatocytes. Pretreatment of the cells with ethanol (6-300 mM) markedly inhibited a subsequent stimulation of phospholipase C by vasopressin, angiotensin II, or epidermal growth factor. By contrast, the effects of the alpha 1-adrenergic agonist phenylephrine and of glucagon were not affected by ethanol pretreatment. Ethanol inhibited the agonist-induced decrease in polyphosphoinositides, the formation of inositol phosphates, and the increase in cytosolic free Ca2+ levels, as detected with the intracellular Ca2+ indicator indo-1. The effects of ethanol were concentration dependent and were pronounced at low concentrations of agonists but were not significant at saturating levels. Pretreatment of the cells with the protein kinase C inhibitor H7 partly prevented the inhibition by ethanol of vasopressin-induced phospholipase C activation. By contrast, pretreatment of the cells with (Rp)-adenosine cyclic 3':5'-phosphorothioate [Rp)-cAMP-S), a competitive inhibitor of protein kinase A, potentiated the inhibitory effect of ethanol on the Ca2+ mobilization by vasopressin. (Rp)-cAMP-S similarly potentiated the inhibition of phospholipase C by the protein kinase C-activating phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). The kinase A inhibitor also made the Ca2+ mobilization by phenylephrine sensitive to ethanol, indicating that the formation of cAMP in the cells played a role in suppressing the sensitivity to ethanol. Pretreatment of the cells with ethanol enhanced the inhibitory effects of TPA on the vasopressin-induced phospholipase C activation at all concentrations of the hormone; however, these synergistic effects were prevented when TPA was added prior to ethanol, a condition that prevents the activation of phospholipase C by ethanol. The data indicate that ethanol causes desensitization of the receptor-mediated phospholipase C secondary to the ethanol-induced activation of phospholipase C and activation of protein kinase C. Ethanol treatment also affects the sensitivity of the phospholipase C system to control by protein kinases A and C. The data indicate that ethanol can affect the control of intracellular signal transduction processes in liver cells under physiologically relevant conditions.
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PMID:Ethanol causes desensitization of receptor-mediated phospholipase C activation in isolated hepatocytes. 184 16

The phenolic antioxidant 2,6-bis(1,1-dimethyl ethyl)-4-methylphenol (BHT) evokes a transient phosphorylation of two platelet proteins of Mr 20,000 and 47,000 that are well-known substrates of protein kinase C (PKC) and, similarly to phorbol esters, a slight but persistent phosphorylation of a protein of Mr 26,000. These effects are observed both in the presence and in the absence of extracellular calcium, but are abolished in the presence of the protein kinase C inhibitor staurosporine. The phosphorylation of the 47 kDa protein takes place mostly at the serine and, to a lesser extent, at threonine residues. BHT induces an increased binding of tritiated phorbol dibutyrate to platelets indicating a PKC translocation from cytosol to plasma membrane. Addition of BHT (20 microM) a few min prior to thrombin causes inhibition of both agonist-evoked protein phosphorylation and increase in the Ca2+ concentration, the latter inhibition being counteracted by staurosporine. The inhibitory effect lasts for several minutes even after removal of BHT from the cellular suspending medium. Similar results are obtained with nordihydroguaiaretic acid, whereas 2- and 3-tert-butyl-4-methoxyphenol (BHA) produce only slight effects. BHT activates the protein kinase C purified from pig brain in a concentration-dependent manner (up to 200 microM), whereas it does not affect the activity of other purified protein kinases such as type 1 and 2 casein kinases, type II A, II B and III tyrosine protein kinases from rat spleen and the catalytic subunit of cyclic AMP-dependent protein kinase. It is concluded that, similarly to diacylglycerols and phorbol esters, these phenolic antioxidants activate the protein kinase C, which in turn desensitizes platelets towards subsequent phospholipase C activation.
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PMID:The antioxidant butylated hydroxytoluene stimulates platelet protein kinase C and inhibits subsequent protein phosphorylation induced by thrombin. 188 50

The effects of the neuropeptide bradykinin (BK) and its natural proteolytic fragment Des-Arg9 bradykinin (DBK) on DNA synthesis and phospholipase C activation were investigated in cultured mesangial cells. DBK, acting through a distinct bradykinin receptor, induced DNA synthesis in serum-starved cultured mesangial cells. The effect of DBK was dose dependent (ED50 = 0.6 microM) and was strongly potentiated by insulin. Under the same conditions, BK had no effect. Down-regulation of protein kinase C by long term pretreatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) markedly reduced DBK-induced DNA synthesis. In the same way, co-incubation with the protein kinase C inhibitor staurosporine potently attenuated the response to DBK, suggesting a role of protein kinase C in DBK-induced mitogenesis. Analysis of phosphoproteins from 32P-labeled mesangial cells by two-dimensional gel electrophoresis revealed that DBK, like TPA but not BK, induced a net increase in the phosphorylation of an acidic cellular protein migrating with an apparent Mr = 80,000 (termed 80K), identified as a major and specific substrate of protein kinase C. Phosphorylation of the 80K protein by DBK or TPA was completely abolished in cells depleted of protein kinase C. DBK and TPA also induced an increase in phosphorylation of an Mr = 28,000 protein. Moreover, DBK but not TPA stimulated the phosphorylation of an Mr = 18,000 protein in normal as well as in protein kinase C-depleted cells. Analysis of phospholipase C activation revealed that DBK induced a large and sustained increase in diacylglycerol production and inositol phosphate accumulation over a 10-min incubation. BK had only a minor effect on both parameters. These results demonstrate that DBK, but not BK, modulates DNA synthesis through protein kinase C activation in cultured mesangial cells.
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PMID:Des-Arg9 bradykinin modulates DNA synthesis, phospholipase C, and protein kinase C in cultured mesangial cells. Distinction from effects of bradykinin. 193 51

ICAM-1 (CD54) is expressed on endothelial cells and serves as an important ligand for the white cell adhesion molecule CD11a/CD18 (LFA-1). Many studies have demonstrated that increased numbers of white cells binding to endothelial cells correlate with the level of ICAM-1 expression on endothelial cells. Several cytokines, including IFN-gamma, increase ICAM-1 expression in cultured human endothelial cells. We have analysed the second intracellular messenger pathways involved in IFN-gamma-induced up-regulation of ICAM-1 expression in endothelial cells. IFN-gamma induced a rapid activation of phospholipase C, leading to a breakdown of phosphoinositoldiphosphate (PIP2) into diacyglycerol (DAG) and inositoltriphosphate (IP3). DAG is a natural activator of the protein kinase C pathway. We were able to show that the effect induced by IFN-gamma could be inhibited by a protein kinase C inhibitor, H7, in a dose-dependent manner and mimicked by PMA, which stimulates protein kinase C. IFN-gamma induced a 5-fold translocation (activation) of protein kinase C from the cytosol into the endothelial cell membrane. Elevation of the IP3 levels led to activation of the calcium-dependent pathway. An inhibitor of calcium calmodulin, W7, decreased the IFN-gamma induced ICAM-1 expression, and addition of calcium ionophore to endothelial cells could replace IFN-gamma in the up-regulation of ICAM-1. Finally, IFN-gamma caused a significant increase in the calcium flux of endothelial cells. cAMP and cGMP had no effect on the regulation of ICAM-1 expression on cultured human endothelial cells.
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PMID:Activation of protein kinase C is crucial in the regulation of ICAM-1 expression on endothelial cells by interferon-gamma. 198 67

We have examined the activation of phospholipase D in human platelets treated with alpha-thrombin. When incubated with 1-O-[9,10-3H2]hexadecyl-2-lysophosphatidylcholine (PtdCho) and 1-alkyl-[32P]lysoPtdCho for 2 h, platelets formed 3H/32P-labeled PtdCho in a ratio of 11:1. After incubation of such labeled platelets with alpha-thrombin for 5 min, increased accumulation of 3H/32P-labeled phosphatidic acid (PtdOH) was detected in the same ratio, indicating the action of phospholipase D. The Ca2+ ionophore A23187 and alpha-thrombin each stimulated the formation of labeled PtdOH as above in a time- and concentration-dependent manner, with only minor changes in labeled diglyceride. A23187 was able to cause increases in labeled PtdOH comparable to those observed with alpha-thrombin. beta-Phorbol 12,13-dibutyrate, an activator of protein kinase C, only slightly stimulated the accumulation of labeled PtOH. The protein kinase C inhibitor, staurosporine, totally blocked these changes but only slightly inhibited the increases in labeled PtdOH promoted by alpha-thrombin. These results suggest that an increase in intracellular Ca2+, rather than protein kinase C activity, is a major factor regulating phospholipase D in platelets exposed to alpha-thrombin. We have also examined the relative contributions of phospholipase D and diglyceride kinase (following phospholipase C action) to PtdOH accumulation in [32P]Pi-labeled platelets by comparing the 32P-specific radioactivities of PtdOH, PtdCho, and metabolic gamma-ATP in control and alpha-thrombin-exposed platelets. Based on these determinations, we conclude that 13 and 87% of incremental PtdOH in human platelets exposed to alpha-thrombin arises via phospholipase D acting on PtdCho and phospholipase C/diglyceride kinase, respectively.
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PMID:Elevated cytosolic Ca2+ activates phospholipase D in human platelets. 198 42

1. 5-Hydroxytryptamine (5-HT) produced a concentration-dependent increase in the membrane concentration of 1,2-diacylglycerol (DG) in the rabbit isolated basilar artery, but did not stimulate the hydrolysis of membrane phosphoinositide. 2. The 5-HT-induced accumulation of DG could be blocked with the putative phospholipase C inhibitor 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC; 70 microM), but not with the protein kinase C inhibitor, 1-(5-isoquinolinesulphonyl)-2-methyl piperazine (H7; 50 microM). 3. Direct stimulation of protein kinase C with phorbol 12,13-dibutyrate (PDBu) produced sustained smooth muscle contraction which was fairly rapid in onset and could be reversed by H7 but not by NCDC. The inactive phorbol, 4 alpha phorbol 12,13-dideceonate, did not produce contraction in the basilar artery. 4. 5-HT-induced contractions (1 nM-100 microM) were blocked or greatly reduced in the presence of the protein kinase inhibitor H7 or polymyxin B, and with the phospholipase C inhibitor, NCDC. The concentrations of these inhibitors which abolished contraction to 5-HT, did not alter smooth muscle contraction produced in response to 30 mM K(+)-physiological salt solution (PSS). 5. These data suggest that DG production and the subsequent activation of PKC forms an important component of the cerebrovascular contractile response to 5-HT. As the DG does not appear to arise from membrane phosphatidylinositol, it appears that 5-HT can stimulate the production of this second messenger in cerebral arteries by a mechanism which is different from peripheral arteries.
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PMID:5-hydroxytryptamine-stimulated accumulation of 1,2-diacylglycerol in the rabbit basilar artery: a role for protein kinase C in smooth muscle contraction. 201 23


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