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)

Primary cultures of endometrial glands and stromal cells were labelled with [14C]-arachidonic acid for 4 h before exposure to either the calcium ionophore, A23187 (which activates phospholipase A2 (PLA2) by increasing intracellular calcium concentrations) or sodium fluoride (which activates a G-protein). Calcium ionophore (0.5-50 mumol/l) stimulated a dose- and time-dependent release of arachidonic acid from endometrial glands. Incubation with ionophore (10 mumol/l) for 1 h released 22% of the incorporated arachidonic acid. There was a corresponding decrease in phospholipids and no loss from triglycerides. Stromal cells were unresponsive to ionophore. Fluoride (10 mmol/l) stimulated a release of arachidonic acid from stromal cells and endometrial glands (6.5% of the total arachidonic acid incorporated). In stromal cells, arachidonic acid was released from triglycerides in Day-1 cultures and from phospholipids in Day-2 cultures. In both Day-1 and Day-2 cultures of endometrial glands, arachidonic acid was released from phospholipids, but not from triglycerides. Among the phospholipids, phosphatidylcholine was always the major source of arachidonic acid. Arachidonic acid release from endometrial glands and stromal cells may be mediated by activation of PLA2 (or phospholipase C) via a G-protein, but in glands calcium ionophore may have a direct effect on PLA2. The response to calcium ionophore may reflect the differences in calcium requirements of the two endometrial PLA2 isoenzymes.
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PMID:Release of arachidonic acid from human endometrial cells in culture mediated by calcium ionophore (A23187) or fluoride. 178 65

We have studied the effects of fluoride, guanosine 5'-[gamma-thio]triphosphate (GTP[S]) and carbachol on phospholipase C and polyphosphoinositide synthesis. The experimental system consisted of membranes from rat brain cortex, with exogenous [3H]phosphatidylinositol ([3H]PtdIns) as substrate. In such systems, we have not found evidence to support carbachol and/or GTP[S] stimulation of PtdIns phosphorylation. Fluoride inhibited synthesis of PtdIns4P and PtdIns(4,5)P2 from PtdIns. Consequently, under conditions where breakdown of polyphosphoinositides by phospholipase C was dependent on PtdIns kinase activity, fluoride inhibited activation by GTP[S] plus carbachol of phospholipase C. When conditions allowed direct breakdown of PtdIns and precluded PtdIns kinase activity, the stimulatory effects of fluoride and GTP[S] plus carbachol on phospholipase C activity were additive.
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PMID:Dual effect of fluoride on phosphoinositide metabolism in rat brain cortex. Stimulation of phospholipase C and inhibition of polyphosphoinositide synthesis. 216 21

In contrast to the rapid, ethanol-inhibited superoxide generation by the receptor-linked agonist formyl-methionyl-leucyl-phenylalanine (fMLP), fluoride-activated superoxide generation occurs after a prolonged lag, and as shown herein is relatively ethanol-insensitive. We have investigated fluoride-activation of diradylglycerol generation and phospholipase D activity. Fluoride induces a very large increase in diradylglycerol mass (both 1,2-diacylglycerol (DAG) and 1-O-alkyl,2-acylglycerol (EAG)), with kinetics similar to superoxide generation. Unlike fMLP-activated diglyceride generation which is completely inhibited by ethanol, that produced by fluoride is only partially (30%) blocked. When the phosphatidylcholine pool is 3H-prelabeled, fluoride activates both [3H]phosphatidic acid (PA) and [3H]diglyceride generation with similar kinetics. Partial inhibition of the production of these species by ethanol was seen, coincident with the appearance of [3H]phosphatidylethanol, indicating phospholipase D-dependent transphosphatidylation had occurred. The data are consistent with the fluoride activation of PA and diglyceride generation by both phospholipase D-dependent and -independent (presumably phospholipase C) mechanisms.
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PMID:Fluoride activates diradylglycerol and superoxide generation in human neutrophils via PLD/PA phosphohydrolase-dependent and -independent pathways. 217 14

Fluoride ion (F-) alone or in conjunction with aluminum (Al3+) has been shown to stimulate the activity of guanine nucleotide-binding proteins (G proteins) in cell membrane preparations from a variety of cell types and in intact hepatic cells. Several studies have indicated that G proteins are involved in the regulation of parathyroid hormone (PTH) secretion. Intracellular second messengers which modulate PTH secretion (e.g., cAMP) have also been found to be regulated by G proteins. We have, therefore, employed F- as a probe to investigate the possible role of G proteins in the modulation of PTH release and the intracellular second messengers that have been implicated in the control of PTH secretion. F- produces a dose-dependent inhibition of PTH release with a maximal inhibitory effect (67%) at 5 mM. F- exerts its inhibitory effect within 5 min and the degree of suppression of PTH secretion gradually increases over 1 hr. F- (5 mM) inhibits PTH secretion at 0.5 mM Ca2+ to the level observed with 2 mM Ca2+ alone; moreover, the effects of F- and high Ca2+ are not additive. While 1 mM F- suppresses PTH secretion by only 21%, and 10 microM Al3+ has virtually no effect at all, together they inhibit PTH release approximately to the level (63% inhibition) observed with 5 mM NaF alone. In the presence of 10(-5) M dopamine, F- produces a concentration-dependent inhibition of cAMP accumulation (0.684 +/- 0.033 pmoles/10(5) cells at 0 mM F- vs. 0.256 +/- 0.048 at 5 mM F-). However, the F- -induced decrease in cAMP cannot account for the inhibition of PTH release by this agent, since addition of methylisobutylxanthine (10(-4) M) by F- -treated cells raises intracellular cAMP content above that of control cells but fails to reverse the inhibition of PTH release. The cytosolic calcium concentration in Fura-2-loaded cells increases from 210 +/- 20 nM to 340 +/- 44 nM after 5 mM F- was added to incubation media. Prior removal of extracellular Ca2+ by EGTA totally blocks the F- -induced rise in cytosolic Ca2+ without preventing the inhibition of PTH release by NaF. F- also produces a time- and dose-dependent increase in the accumulation of IP, IP2, and IP3 in cells prelabeled with [3H]inositol and incubated with 10 mM Li+, consistent with activation of phospholipase C. We conclude that F- is a potent inhibitor of PTH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of fluoride on parathyroid hormone secretion and intracellular second messengers in bovine parathyroid cells. 246 39

Fluoride interacts with G proteins and, consequently, stimulates phospholipase C as measured by the formation of inositol phosphates and phosphatidic acid. In human platelets this paralleled platelet aggregation and the activation of phosphorylation of substrates of protein kinase C (47kDa protein) and myosin light chain kinase (20kDa protein). Phospholipase C activation by fluoride was inhibited by dibutyryl cyclic AMP and by agents that increase cyclic AMP levels such as iloprost and forskolin. This information suggest that cyclic AMP affects the G protein associated with the stimulation of phospholipase C.
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PMID:Activation of platelet phospholipase C by fluoride is inhibited by elevation of cyclic AMP. 246 3

The Drosophila and Lucilia photoreceptor mutants, trp and nss, respond like wild-type flies to a short pulse of intense light or prolonged dim light; however, upon continuous intense illumination, the trp and nss mutants are unable to maintain persistent excitation. This defect manifests itself by a decline of the receptor potential toward baseline during prolonged intense illumination with little change in the shape or amplitude of the quantal responses to single photons (quantum bumps). Previous work on the trp and nss mutants suggests that a negative feedback loop may control the rate of bump production. Chemical agents affecting different steps of the phototransduction cascade were used in conjunction with light to identify a possible branching point of the feedback loop and molecular stages which are affected by the mutation. Fluoride ions, which in the dark both excite and adapt the photoreceptors of wild-type flies, neither excite nor adapt the photoreceptors of the trp and nss mutants. The hydrolysis-resistant analogue, GTP gamma S, which excites the photoreceptors of wild-type flies, resulting in noisy depolarization, markedly reduces the light response of both mutant flies. Intracellular recordings revealed, however, that the inhibitory effect of GTP gamma S on the nss mutant was accompanied neither by any significant depolarization nor by an increase in the noise, and thus was very different from the effect of a dim background light. The combination of inositol trisphosphate and diphosphoglycerate (InsP3 + DPG), which efficiently excites the photoreceptors of wild-type Lucilia, also excites the photoreceptors of nss Lucilia mutant. The InsP3 + DPG together act synergistically with light to accelerate the decline of the response to light in the mutant flies. These results suggest that the fly phototransduction pathway involves a feedback regulatory loop, which branches subsequent to InsP3 production and regulates guanine nucleotide-binding protein (G protein)-phospholipase C activity. A defect in this regulatory loop, which may cause an unusually low level of intracellular Ca2+, severely reduces the triggering of bumps in the mutants during intense prolonged illumination.
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PMID:Chemical excitation and inactivation in photoreceptors of the fly mutants trp and nss. 260 31

To investigate whether guanosine triphosphate-binding proteins (G proteins) are involved in T cell activation, tests were made of the effect of pertussis toxin, cholera toxin, guanosine 5'-(3-O-thio)-triphosphate, and fluoride ions on interleukin 2 (IL-2) synthesis in Jurkat cells. It was found: 1) that pertussis toxin interferes with the first pathway of T cell activation insofar as it can substitute for phytohemagglutinin or monoclonal antibodies directed against the CD3 surface proteins, suggesting that a G protein serves as transducer for signals via the T cell receptor-CD3 complex; and 2) that fluoride ions induce the release of diacylglycerol (DAG) from [3H] arachidonic acid or [3H]oleic acid-prelabeled cells. In [3H]inositol or 32P-prelabeled cells, the increase in DAG production was also found to be accompanied by a 280% increase of intracellular inositol phosphate (IP), without significant modification of IP2 and IP3. These results suggest that a G protein controls the activity of a phospholipase C in Jurkat cells that upon stimulation releases DAG but not IP3. Inasmuch as DAG, like the phorbol ester tetradecanoyl phorbol acetate, activates protein kinase C, it suggests that a G protein is also involved in the transduction of the second signal for lymphocyte activation. Fluoride ions were found to be as effective as tetradecanoyl phorbol acetate to stimulate IL-2 synthesis in Jurkat cells when used in combination with phytohemagglutinin. Finally, cholera toxin and guanosine 5'-(3-O-thio)-triphosphate were found to increase intracellular cyclic adenosine triphosphate and to inhibit IL-2 synthesis. All together these results suggest that several G proteins are involved in the transduction of the two signals necessary for T cell activation as well as in the negative regulation of IL-2 synthesis.
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PMID:Inhibition and activation of interleukin 2 synthesis by direct modification of guanosine triphosphate-binding proteins. 282 88

Fluoride ions (1-30 mM) stimulate phosphoinositide hydrolysis in guinea-pig ileum longitudinal smooth muscle slices, and this is not inhibited in the presence of indomethacin or nifedipine. This action is associated with a slow contractile response which peaks after approximately five minutes and then declines towards baseline; at this time the contractile response to a maximally effective concentration of carbachol is also inhibited. Fluoride-induced contractions are inhibited completely in the presence of nifedipine. Similarly, contractions induced by caffeine, which releases Ca2+ from intracellular stores, are also inhibited by nifedipine. These data are consistent with a model in which the activation of a G-protein by F- ions leads to the following sequential events: activation of phospholipase C, release of intracellular Ca2+, opening of voltage operated (i.e. dihydropyridine sensitive) Ca2+ channels and contraction. The transient nature of the fluoride contraction and the inhibition of the carbachol contraction may be due to a slow elevation of cAMP levels induced by F-.
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PMID:Does the hydrolysis of inositol phospholipids lead to the opening of voltage operated Ca2+ channels in guinea-pig ileum? Studies with fluoride ions and caffeine. 283 95

Fluoride ion, at concentrations above 10 mM, was found to elicit a rise in intracellular calcium levels in neutrophils, as monitored by changes in Quin 2 fluorescence intensity. The calcium mobilization response was characterized by a lag period of 4 to 10 min. and a prolonged duration of action (greater than 20 min.). In contrast, the chemotactic peptide, formylmethionyl-leucyl-phenylalanine, induced a rise in intracellular calcium concentrations which peaked within 1 min. Preincubation of the cells with 1 microgram/ml pertussis toxin resulted in inhibition of the formylmethionyl-leucyl-phenylalanine induced response, but not that mediated by fluoride. Recent evidence suggests that the formylmethionyl-leucyl-phenylalanine receptor is coupled to phospholipase C and phosphoinositide degradation through a guanine nucleotide binding protein susceptible to inhibition by pertussis toxin. Present results suggest that fluoride ion may serve to activate this protein in a manner resistant to inhibition by pertussis toxin.
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PMID:Calcium mobilization in fluoride activated human neutrophils. 300 Mar 73

In platelets activated by thrombin, the hydrolysis of phosphatidylinositol 4,5-bisphosphate by phospholipase C produces inositol 1,4,5-triphosphate (IP3) and diacylglycerol, metabolites which are known to cause Ca2+ release from the platelet dense tubular system and granule secretion. Previous studies suggest that phospholipase C activation is coupled to platelet thrombin receptors by a guanine nucleotide-binding protein or G protein. The present studies examine the contribution of this protein to thrombin-induced platelet activation and compare its properties with those of Gi, the G protein which mediates inhibition of adenylate cyclase by thrombin. In platelets permeabilized with saponin, nonhydrolyzable GTP analogs reproduced the effects of thrombin by causing diacylglycerol formation, Ca2+ release from the dense tubular system and serotonin secretion. In intact platelets, fluoride, which by-passes the thrombin receptor and directly activates G proteins, caused phosphoinositide hydrolysis and secretion. Fluoride also caused an increase in the platelet cytosolic free Ca2+ concentration that appeared to be due to a combination of Ca2+ release from the dense tubular system and increased Ca2+ influx across the platelet plasma membrane. Guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), which inhibits G protein function, inhibited the ability of thrombin to cause IP3 and diacylglycerol formation, granule secretion, and Ca2+ release from the dense tubular system in saponin-treated platelets. Increasing the thrombin concentration overcame the effects of GDP beta S on secretion without restoring diacylglycerol formation. The effects of GDP beta S on platelet responses to thrombin which had been subjected to partial proteolysis (gamma-thrombin) were similar to those obtained with native alpha-thrombin despite the fact that gamma-thrombin is a less potent inhibitor of adenylate cyclase than is alpha-thrombin. Thrombin-induced diacylglycerol formation and 45Ca release were also inhibited when the saponin-treated platelets were preincubated with pertussis toxin, an event that was associated with the ADP-ribosylation of a protein with Mr = 41.7 kDa. At each concentration tested, the inhibition of thrombin-induced diacylglycerol formation by pertussis toxin paralleled the inhibition of thrombin's ability to suppress PGI2-stimulated cAMP formation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of the phosphoinositide hydrolysis pathway in thrombin-stimulated platelets by a pertussis toxin-sensitive guanine nucleotide-binding protein. Evaluation of its contribution to platelet activation and comparisons with the adenylate cyclase inhibitory protein, Gi. 302 67


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