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)

Agonist-activated phosphoinositide (PI)-specific phospholipase C initiates PI hydrolysis to produce signals implicated in mitogenic signaling in which the cyclin-dependent cdc2-protein kinase of the maturation-promoting factor is a major protein-tyrosine kinase (PTK) substrate. It has been suggested that PI mitogenic signals are separable into PTK-dependent and non-PTK-dependent by genistein, a tyrosine-specific protein kinase inhibitor. However, we show here that DNA synthesis was abolished in human Chang liver cells although the sulphate-induced PI second messengers, i.e. inositol 1,4,5-trisphosphate and sn-1,2,diacylglycerol, were at equivalent dose-response levels with or without genistein (0.5 mM, 135 microgram/ml). This genistein dosage had been demonstrated to be effective in suppressing tyrosyl phosphorylation in cells. There was no increase in the trypan blue dead cell index. We have shown previously that human Chang cells stimulated by this 'non-growth-factor' agonist, i.e. sulphate, as well as extracellular ATP, became rounded with raised intracellular pH. ATP-induced cell rounding and intracellular alkalinization were not affected by the presence of genistein (0.5 mM). In the present investigation, that genistein dosage had also no effect on these cellular responses when initiated by added sulphate. It seems that the mitogenic signaling function of PI second messengers is dissociable and requires unsuppressed PTK activity.
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PMID:Genistein inhibits DNA synthesis but has no effect on levels of DAG and IP3, cell rounding and alkalinization in sulphate-treated Chang liver cells. 130 25

We studied the effects of changing the intracellular Ca level ([Ca]i) and activating protein kinase C on the cardiac T and L Ca channels in single canine ventricular and Purkinje cells. Lowering [Ca]i increased the L current but decreased the T current, whereas elevating [Ca]i caused opposite changes. In ventricular cells, isoproterenol (1 microM) increased the amplitude of not only the L but also the T currents; the latter effect probably was secondary to a rise in [Ca]i following the augmentation of the L current. 12-O-tetradecanoylphorbol-13-acetate (TPA, 100 nM) decreased the T current but first increased and then decreased the L current. The TPA effects on the T and L currents were not mimicked by a phorbol ester that does not activate PKC (4 alpha-phorbol 12,13-didecanoate) and were prevented by a protein kinase inhibitor (H-8), confirming the involvement of PKC activity in these modulatory processes. We conclude that elevating [Ca]i and activating PKC have opposite effects on the T and L Ca currents in canine cardiac cells. The extent and time course of the changes in these two intracellular messengers will most likely determine the effects on the two cardiac Ca currents of neurotransmitters and hormones that can activate phospholipase C.
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PMID:Different effects of intracellular Ca and protein kinase C on cardiac T and L Ca currents. 165 11

Transepithelial phosphate (Pi) fluxes were determined in primary monolayer cultures of the winter flounder proximal tubule in Ussing chambers. Net Pi secretion, peritubular (P)-to-lumen (L) net flux (Jnet = 17.0 +/- 3.77 nmol.cm-2.h-1), was strongly stimulated by lowering peritubular pH to 6.5 (pHP 6.5 vs. pHL 7.5) compared with control tissues at pH 7.5 (pHP 7.5 vs. pHL 7.5) where net reabsorption (L-to-P Jnet = 1.10 +/- 0.36 nmol.cm-2.h-1) occurred. The stimulation of net secretion by pHP 6.5 was inhibited to 27% of control by 200 microM amiloride. The imposition of a reversed pH gradient (pHL 6.5 vs. pHP 7.5) did not stimulate Pi secretion. Preincubation with 0.5 U/ml phospholipase C caused a nearly fivefold stimulation of Pi secretion compared with the untreated controls. H-7 (100 microM), a protein kinase inhibitor, caused a 2.5-fold reduction in phorbol ester (PE)-induced stimulation of Pi secretion. H-7 also significantly inhibited Pi secretion (50% reduction) when peritubular pH was lowered to 6.5. PE-induced net Pi secretion was significantly lower when luminal pH was lowered to 5.5 compared with controls where luminal pH was kept at 7.5. Amiloride (200 microM) significantly inhibited the PE-induced net Pi secretion in the presence of luminal pH 7.5 but had no significant effect at luminal pH 5.5. Replacement of luminal NaCl with LiCl or isosmolar mannitol significantly reduced net phosphate secretion under the conditions of lowered peritubular pH. Net Pi secretion was also dependent on the maintenance of a cellular Na+ gradient, since 100 microM ouabain inhibited PE-induced net Pi secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of pH on phosphate transport by flounder renal tubule primary cultures. 184 76

To investigate a possible regulatory role of protein kinase C (PKC) on collagen-induced phospholipase activity, human platelets were prelabelled with either [3H] arachidonic acid or [14C]stearic acid and stimulated with collagen (2 micrograms/ml) in the presence or absence of the protein kinase inhibitor, staurosporine (1 microM). The collagen-induced release of [3H]arachidonic acid and formation of [14C]stearoyl-labelled lysophospholipids was inhibited by prior incubation with staurosporine, as was the formation of 3H-labelled thromboxane B2, thereby suggesting inhibition of the collagen-induced phospholipase A2 activity. The degradation of phosphatidylinositol (PI) and elevation of phosphatidic acid (PA) in platelets prelabelled with either radiotracer were also completely blocked by staurosporine pretreatment, indicating a suppression of collagen-stimulated phospholipase C activity. Suppressed phospholipase C activity may have been due to diminished thromboxane A2 formation since treatment with the dual cyclo-oxygenase/lipoxygenase inhibitor, BW755C, also resulted in an inhibition of the collagen-stimulated loss of 14C-labelled PI and rise in PA by 75-80%. Our results suggest that protein kinase, possible PKC, may be involved in the regulation of these phospholipases in collagen-stimulated human platelets.
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PMID:Inhibition of phosphatidic acid production and lysophospholipid formation in collagen-stimulated human platelets by staurosporine, a protein kinase inhibitor. 190 94

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

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulates a rapid increase in ornithine decarboxylase (EC 4.1.1.17; ODC) activity in target cells. Here we demonstrate that this process involves a rapid accumulation of ODC mRNA, which is maximal 3 h after treatment (three- to eightfold greater than control cells) and decays to control levels within 18 h. Stimulation of ODC mRNA by TPA is blocked by phorbol dibutyrate down-regulation of protein kinase C (PKC). ODC mRNA was also induced by the PKC activators, phospholipase C and 1-oleoyl-2-acetyl-rac-glycerol, and blocked by kinase inhibitors (trifluoroperazine, H7, and palmitoyl-L-carnitine), consistent with a requirement for PKC activation in the induction mechanism. However, the non-PKC-specific protein kinase inhibitor HA1004 also suppressed expression of ODC mRNA in response to TPA, under conditions where it did not inhibit PKC, suggesting that additional kinases may be involved in the intracellular signalling process. The stability of the ODC mRNA (control value = 6.2 +/- 1.6 h) is not significantly changed by either TPA (5.7 +/- 0.8 h) or by cycloheximide (6.0 h). These results are inconsistent with any contribution from altered mRNA half-life towards the accumulation of ODC mRNA following treatment with phorbol ester tumor promoters.
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PMID:Involvement of protein kinase C in the regulation of ornithine decarboxylase mRNA by phorbol esters in rat hepatoma cells. 201 52

Essentially pure preparations of normal density eosinophils obtained from patients with hypereosinophilic syndrome (HES) were stimulated with complement factor 5a (C5a), platelet-activating factor (PAF), FMLP and neutrophil-activating peptide (NAP-1/IL-8). Three responses were studied, the transient rise in cytosolic free calcium concentration ([Ca2+]i) (derived from indo-1 fluorescence), shape changes (measured by laser turbidimetry), and exocytosis of eosinophil peroxidase (EPO) (assessed by H2O2/luminol-dependent chemiluminescence). Responses were obtained with all four agonists, but C5a and PAF were by far more potent than FMLP and NAP-1/IL-8, which induced only minor effects. Pretreatment of the cells with pertussis toxin attenuated [Ca2+]i changes, EPO release and, to a lesser extent, shape changes, indicating that GTP-binding proteins of Gi-type are involved in receptor-dependent signal transduction processes leading to these responses. A clear dissociation was observed in the control of the shape change response and EPO exocytosis. The shape change was not affected by Ca2+ depletion or treatment with the protein kinase inhibitor staurosporine, but exocytosis was prevented by Ca2+ depletion and markedly enhanced by staurosporine. The activation of the contractile system, leading to shape changes and motility, thus appears to be independent of the classical signal transduction pathway involving phospholipase C, a [Ca2+]i rise and protein kinase C activation. Exocytosis is, as expected, Ca2+ dependent and appears to be under a negative control involving protein phosphorylations.
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PMID:Shape changes, exocytosis, and cytosolic free calcium changes in stimulated human eosinophils. 204 Jun 92

Rabbit platelets were labelled with [3H]glycerol and incubated with or without phorbol 12-myristate 13-acetate (PMA). Membranes were then isolated and assayed for phospholipase D (PLD) activity by monitoring [3H]phosphatidylethanol formation in the presence of 300 mM-ethanol. At a [Ca2+free] of 1 microM, PLD activity was detected in control membranes, but was 5.4 +/- 0.8-fold (mean +/- S.E.M.) greater in membranes from PMA-treated platelets. Under the same conditions, 10 microM-guanosine 5'-[gamma-thio]triphosphate (GTP[S]) stimulated PLD by 18 +/- 3-fold in control membranes, whereas PMA treatment and GTP[S] interacted synergistically to increase PLD activity by 62 +/- 12-fold. GTP[S]-stimulated PLD activity was observed in the absence of Ca2+, but was increased by 1 microM-Ca2+ (3.5 +/- 0.2-fold and 1.8 +/- 0.1-fold in membranes from control and PMA-treated platelets respectively). GTP exerted effects almost as great as those of GTP[S], but 20-30-fold higher concentrations were required. Guanosine 5'-[beta-thio]diphosphate inhibited the effects of GTP[S] or GTP, suggesting a role for a GTP-binding protein in activation of PLD. Thrombin (2 units/ml) stimulated the PLD activity of platelet membranes only very weakly and in a GTP-independent manner. The actions of PMA and analogues on PLD activity correlated with their ability to stimulate protein kinase C in intact platelets. Staurosporine, a potent protein kinase inhibitor, had both inhibitory and, at higher concentrations, stimulatory effects on the activation of PLD by PMA. The results suggest that PMA not only stimulates PLD via activation of protein kinase C but can also activate the enzyme by a phosphorylation-independent mechanism in the presence of staurosporine. However, under physiological conditions, full activation of platelet PLD may require the interplay of protein kinase C, increased Ca2+ and a GTP-binding protein, and may occur as a secondary effect of the activation of phospholipase C.
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PMID:Phorbol ester treatment of intact rabbit platelets greatly enhances both the basal and guanosine 5'-[gamma-thio]triphosphate-stimulated phospholipase D activities of isolated platelet membranes. Physiological activation of phospholipase D may be secondary to activation of phospholipase C. 212 96

Both 5-HT and the 9 amino acid neuropeptide SCPb modulate 3 ionic currents in B15, enhancing a voltage-dependent inward sodium current, decreasing an outward potassium current and increasing an inward rectifying potassium current. In contrast, FMRFamide decreases a voltage-dependent inward sodium current and increases an outward potassium current. We have also investigated the roles of several second-messenger systems that may be mediating the effects of these modulators. Bath application of membrane permeable analogs of cAMP enhance the voltage-dependent inward sodium current and both 5-HT and SCPb increase cAMP levels in B15, suggesting that cAMP may be mediating part of the observed effects of these transmitters on B15. Experiments with phorbol ester, a protein kinase inhibitor, and a phospholipase inhibitor suggest that the phospholipase C/protein kinase C cascade may decrease an outward potassium current. Thus, 5-HT and SCPb may activate multiple second-messenger systems to modulate 3 ionic currents in B15. Additional studies suggest that a cascade involving arachidonic acid may be involved in mediating part of the FMRFamide responses in B15. These studies are beginning to define molecular mechanisms whereby a neuron differentially modulates multiple ionic currents in response to distinct chemical messengers.
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PMID:Modulation of ionic currents in Aplysia motor neuron B15 by serotonin, neuropeptides, and second messengers. 247 12

Angiogenin stimulates capillary and umbilical vein endothelial cell prostacyclin secretion but not that of prostaglandins of the E series. The response was quantitated by radioimmunoassay and by [3H]arachidonate labeling followed by analysis of the secreted prostaglandins. The stimulated secretion lasts for several minutes and is optimal at 2-4 min. The dose-response (peak at 1-10 ng/ml) is similar to that previously observed for activation of endothelial cell phospholipase C. Stimulated secretion was blocked by pretreatment with the inhibitors of prostacyclin synthesis, indomethacin and tranylcypromine, and also the specific inhibitor of phospholipase A2, quinacrine, as well as pertussis toxin and the diglyceryl and monoglyceryl lipase inhibitor RHC 80267. Stimulated secretion was also abolished in cells that were either pretreated for 48 hr with phorbol ester to down-regulate protein kinase C or incubated with the protein kinase inhibitor H7. Hydrolysis of phosphatidylinositol by phospholipase A2 appears to be the source of angiogenin-mobilized arachidonate; angiogenin-induced hydrolysis of phosphatidylcholine was not detected. Activation of phospholipase A2 occurs in the absence of an angiogenin-induced calcium flux. The results are discussed in terms of mechanisms of agonist-induced intracellular arachidonate mobilization and relevance to angiogenesis.
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PMID:Angiogenin stimulates endothelial cell prostacyclin secretion by activation of phospholipase A2. 264 38


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