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)

Release of arachidonic acid (AA) from 1-stearoyl-2-[14C]arachidonyl-glycerophosphoinositol (PI) by plasma membrane-bound enzyme(s) is a calcium-dependent reaction and is markedly activated at 4 x 10(-4) M CaCl2. In the presence of Ca2+, the agonist of the cholinergic receptor (carbachol) enhances, in a dose-related manner, AA release. Moreover, GTP and its non-hydrolysable analogs GTP gamma S and GppNHp and also NaF additionally increase the carbachol-mediated liberation of AA from PI. On the contrary, in the absence of Ca2+ carbachol and GTP gamma S have no stimulatory effect on AA release. Guanosine-5'-O-2-thiodiphosphate GDP gamma S, which inhibits the function of GTP-binding proteins, also suppresses carbachol-mediated activation of AA release from PI. The stimulatory effect of carbachol and guanine nucleotides was observed exclusively in the brain plasma membrane (there was no effect on mitochondria, microsome and cytosolic enzymes). Quinacrine, the inhibitor of phospholipase A2, completely inhibits carbachol- and guanine nucleotide-activated AA release and greatly (by about 60-70%) decreases Ca(2+)-dependent AA liberation from phosphatidylinositol. These results indicate that GTP-binding protein(s) are involved in the regulation of carbachol-mediated AA release. The main pool of this acid is liberated from phosphatidylinositol by phospholipase A2 and only a small pool of AA may be released indirectly as the result of PI hydrolysis by sequential action of phospholipase C and diacylglycerol lipase.
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PMID:Guanine nucleotides and fluoride enhance carbachol-mediated arachidonic acid release from phosphatidylinositol. Evidence for involvement of GTP-binding protein in phospholipase A2 activation. 251 94

RHC 80267, on inhibitor of diacylglycerol lipase, was used to investigate the role of diacylglycerol in acid secretion by isolated rat gastric parietal cells. Unexpectedly, RHC 80267 stimulated the production of inositol phosphates in [3H]inositol-prelabeled cells and increased levels of 32P-labeled phosphatidic acid to the same degree as did carbachol. RHC 80267 increased diacylglycerol to a greater extent than did carbachol, and additionally decreased levels of [3H]arachidonic acid. This suggests that RHC 80267 stimulated phospholipase C and inhibited diacylglycerol lipase in parietal cells. RHC inhibited [14C]aminopyrine uptake, a measure of acid secretion, stimulated by carbachol or by simultaneous addition of carbachol and dibutyryl-cAMP. These data support the model that the diacylglycerol/protein kinase C branch of the phosphoinositide system is inhibitory to acid secretion.
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PMID:Stimulation of inositol phosphate and diacylglycerol production by RHC 80267, a diacylglycerol-lipase inhibitor, in rat gastric parietal cells: effects on hydrogen ion secretion. 253 97

The effect of phosphatidylinositol-specific phospholipase C (PI-PLC) on the release of lipoprotein lipase was studied in F1 heart cell cultures. Exposure of the cultures for 10 min to PI-PLC resulted in a 2-fold increase in the release of lipoprotein lipase (LPL) into the culture medium. PI-PLC released LPL from the heparin-releasable pool and PI-PLC was not effective in cultures pretreated with heparin. Insulin had no influence on the release of LPL from the heart cell cultures, even though it enhanced the uptake of 2-deoxy[3H]glucose by these cells. In cultures labeled with 35S, treatment with PI-PLC resulted in an increase in the release of 35S-labeled proteoglycan. PI-PLC was also effective in enhancing the release of bovine LPL exogenously bound to cultured aortic smooth muscle cells. The findings that PI-PLC was not effective after heparin, that it did release exogenously added LPL to cell cultures and that it released 35S-labeled proteoglycan, were interpreted to indicate that PI-PLC apparently acts on the release of LPL in an indirect manner, releasing heparan sulphate to which LPL is bound. As there is a previously described correlation between circulating LPL and the heparin-releasable LPL, we hypothesize that the activity of PI-PLC in the endothelial cell membrane or plasma phosphatidyl-specific phospholipase D regulates the plasma LPL levels.
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PMID:Phosphatidylinositol-specific phospholipase C releases lipoprotein lipase from the heparin releasable pool in rat heart cell cultures. 255 75

Human umbilical vein endothelial cells at confluence were subjected to steady shear flow. It was previously shown that flow induced a burst in prostacyclin production followed by a sustained stimulation of production several fold higher than basal levels (1). In the presence of EGTA, prostacyclin production was inhibited in the steady state phase by 74%. Preincubation of endothelial cells with quin2/AM, used here as an intracellular calcium chelator, also inhibited the production of prostacyclin (83%). Inhibition of intracellular calcium mobilization had no significant effect. Incubation of cells with nifedipine, a voltage operated channel blocker, had no effect on shear induced prostacyclin production, whereas ibuprofen decreased shear induced prostacyclin production. RHC-80267, a diacylglycerol lipase inhibitor, inhibited 66% of shear induced PGI2 production. Our results suggest that both extracellular and intracellular Ca2+ are necessary and the phospholipase C pathway may be the main source for liberating arachidonic acid in shear induced prostacyclin production.
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PMID:Mechanism of shear-induced prostacyclin production in endothelial cells. 264 33

The effect of interference with diacylglycerol metabolism was investigated in pancreatic mouse islets. In the presence of the diacylglycerol lipase inhibitor RHC 80,267, glucose-induced insulin secretion was reduced 50-60%; whereas carbacholin-induced insulin secretion was unaffected. Addition of the diacylglycerol kinase inhibitor R 59,022 did not change glucose-stimulated insulin secretion but abolished the inhibition seen in the presence of RHC 80,267. RHC 80,267 increased islet glucose utilisation, measured as formation of tritiated water from 5-[3H]-glucose, 3-fold but did not affect glucose oxidation to CO2, lactate production or islet ATP levels. Glucose utilisation in leucocytes and hepatocytes was not increased by addition of RHC 80,267. Islet lipid production from glucose was augmented 4-fold in the presence of RHC 80,267 but only accounted for about 5% of the increase in glucose utilisation. The activity of adenylate cyclase and phosphoinositide-specific phospholipase C was unaffected by RHC 80,267. Concentrations of RHC 80,267 below 35 mumol/l did not alter the activity of phospholipase A2; whereas higher concentrations of the drug inhibited phospholipase A2 activity approx 25%. The data support the hypothesis that production of arachidonic acid from diacylglycerol may be involved in regulation of insulin secretion.
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PMID:Effect of diacylglycerol lipase inhibitor RHC 80267 on pancreatic mouse islet metabolism and insulin secretion. 265 50

In neonatal rat islet cells prelabelled with [14C-methyl] choline, the phorbol ester 12-O-tetradecanoylphorbol-13-acetate rapidly activated a phospholipase D-like mechanism as suggested by the accumulation in cells and medium of choline (but not of phosphorylcholine or glycerophosphorylcholine, markers for phospholipase C and phospholipase A2 action on phosphatidylcholine). This finding was confirmed by a rise in phosphatidic acid (but not diglyceride or arachidonic acid) in fatty acid-labelled cells. Phospholipase D was also activated by ionomycin or sodium fluoride; however, this was accompanied by parallel increases in diglyceride, monoacylglycerol and arachidonic acid in the absence of phosphorylcholine generation, suggesting that these agents also activated a phospholipase C-diglyceride lipase pathway acting on non-choline-containing phosphoglycerides (presumably phosphoinositides). In conjunction with our recent demonstration of insulinotropic effects of phosphatidic acid (M. Dunlop and R. Larkins, Diabetes, in press), our findings suggest for the first time a possible role for phospholipase D activation in the stimulation of insulin release and may imply a novel site of action for phorbol esters in the regulation of exocytosis.
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PMID:A phospholipase D-like mechanism in pancreatic islet cells: stimulation by calcium ionophore, phorbol ester and sodium fluoride. 267 33

Phosphoinositide hydrolysis is thought to be important in regulating a variety of intracellular signals, including Ca++ and prostaglandins, both of which have been implicated in the action of oxytocin during uterine smooth muscle contraction. We investigated the in vitro effect of oxytocin and various other uterotonic agents on phosphoinositide hydrolysis in gestational myometrium by measuring the production of inositol phosphates in tissue explants prelabeled with 3H-inositol. Oxytocin caused significant increases in all three inositol phosphates in myometrium at 3 minutes. Stimulation of inositol monophosphate production was sustained for 30 minutes and was dose dependent, with a half-maximal effect around 2 X 10(-8) mol/L. Platelet activating factor and alpha-adrenergic agonists also stimulated myometrial phosphoinositide hydrolysis, but carbachol prostaglandins E2 and F2 alpha had no effect. Vasopressin had greater efficacy than oxytocin for stimulating hydrolysis in gestational myometrium. Furthermore, in contrast to vasopressin, oxytocin had no effect on inositol phosphate production in nongestational myometrium. Oxytocin also stimulated arachidonic acid release and prostaglandin E2 and F2 alpha production in gestational myometrium. The hydrolysis of phosphatidylinositol by myometrium homogenates showed a precursor-product relationship for the production of diacylglycerol, monoacylglycerol, and arachidonic acid, indicative of a sequential action of phospholipase C and diacylglycerol lipase. These data demonstrate the potential for certain uterotonic agonists to use inositol lipid signaling to mobilize free arachidonic acid for prostaglandin production and to release intracellular Ca++ during excitation-contraction coupling.
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PMID:A role for phosphoinositide hydrolysis in human uterine smooth muscle during parturition. 284 85

Tritiated arachidonic acid (3H-AA)-labeled rat synovial fibroblasts stimulated with human recombinant interleukin-1 beta (rIL-1 beta) released incorporated radiolabel in a time-dependent and dose-dependent manner, with labeled prostaglandins representing 29% of the released radiolabel. Treatment of the cells with dibutyryl cAMP or prostaglandin E2 enhanced both spontaneous and rIL-1 beta-induced 3H-AA release; treatment with indomethacin or naproxen inhibited the response. The effects of these cyclooxygenase inhibitors on 3H-AA release were not reversed by the addition of prostaglandin E2. The activities of phospholipase A, phospholipase C, and diglyceride lipase were detected in the homogenates of rat synovial fibroblasts. Pretreatment of synovial cells with rIL-1 beta resulted in a threefold stimulation of phospholipase A activity and a slight increase in phospholipase C activity in cell homogenates. These data show that rIL-1 beta stimulates phospholipase activities in rat synovial fibroblasts and that at least one of these activities may be regulated by either prostaglandins or cAMP.
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PMID:Interleukin-1 stimulation of phospholipase activity in rat synovial fibroblasts. Possible regulation by cyclooxygenase products. 284 61

rac-1-[1-14C]Lauroyl-2-oleylglycero-3-phospho[methyl-3H]choline and rac-1-lauroyl-2-[1-14C]oleoylglycero-3-phospho[methyl-3H]choline along with rac-1-palmitoyl-2-oleylglycero-3-phosphocholine and sn-1-palmitoyl-2-oleylglycero-3-phosphocholine were synthesized and subjected to hydrolysis with phospholipase C (EC 3.1.4.3) from Clostridium perfringens and phospholipase D (EC 3.1.4.4) from cabbage. Kinetics of hydrolysis of the radioactive substrates were determined by measuring the 3H radioactivity retained in the aqueous phase due to free choline and phosphocholine and the 3H and 14C radioactivity recovered in the organic phase due to the released diacylglycerols and phosphatidic acids and the residual phosphatidylcholines. The rate of hydrolysis of the unlabelled substrates by phospholipase C was determined by thin-layer chromatography and gas-liquid chromatography of the methanolysis products. The relative initial rates of hydrolysis of sn-1,2,- and sn-2,3-enantiomers were 100-200:1 for phospholipase C and 40-50:1 for phospholipase D using rac-1-lauroyl-2-oleoylglycero-3-phosphocholine as the substrate. The substitution of the 2-acyl group by an alkyl group resulted in a loss of stereospecificity, which was partial for phospholipase C (relative rates equal to 8-13:1) and total for phospholipase D. There was a parallel dramatic decrease (500-1000-fold) in the initial rate of hydrolysis with phospholipase C but the activity of phospholipase D was only moderately reduced (18-fold). These findings are consistent with the earlier observed loss of the stereospecificity of lipoprotein lipase following introduction of a 2-alkyl group into triacylycerols, and point to a general unsuitability of 2-alkyl-linked acylglycerols as substrates for the assay of the stereospecificity of lipases, as well as for the isolation of enantiomeric 2-alkylacylglycerols by means of stereospecific lipases.
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PMID:Loss of stereospecificity of phospholipases C and D upon introduction of a 2-alkyl group into rac-1,2-diacylglycero-3-phosphocholine. 286 Sep 24

Thrombin-induced changes in arachidonate content of platelet phospholipids were quantitated to establish the ultimate origins of this eicosanoid precursor. Fifteen seconds following thrombin addition (15 U/5 X 10(9) platelets), phosphatidylcholine lost 11.8 nmol of arachidonate and phosphatidylethanolamine lost 10.5 nmol. Arachidonate in phosphatidate, phosphatidylinositol, and phosphatidylinositol-4,5-bisphosphate combined decreased by 11.0 nmol. Increases in free and oxygenated arachidonate (41 nmol) exceeded decreases in inositides. Thus phospholipase A2 released at least twice as much arachidonate as phospholipase C-diglyceride lipase. Phosphatidylinositol-4-phosphate levels remained unchanged upon stimulation. Therefore, increases in phosphatidylinositol-4,5-bisphosphate indicated the minimum rate of phosphorylation of phosphatidylinositol to resynthesize phosphatidylinositol-4,5-bisphosphate, following stimulus-induced breakdown by phospholipase C. Phosphatidylinositol-4, 5-bisphosphate increased 1.4 nmol between 10 and 15 sec following thrombin, markedly less than phosphatidylinositol decreased (2.1 nmol). This could be due to phospholipase A2, in addition to phospholipase C, acting directly on phosphatidylinositol to a greater extent than estimated by accumulation of lysophosphatidylinositol, degraded rapidly by lysophospholipase. Thus, upon high-dose thrombin stimulation of human platelets inositide metabolism via phospholipase C directs initial formation of intracellular second messengers, and sequentially, or in parallel, arachidonate release by phospholipase A2 supplies the larger proportion of arachidonate for syntheses of eicosanoids involved in intercellular communication.
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PMID:Stimulated platelets release equivalent amounts of arachidonate from phosphatidylcholine, phosphatidylethanolamine, and inositides. 302 86


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