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)

In order to study the dependence of GnRH-stimulated LH release on inositol phosphate (IP) turnover, this study used an inhibitor of phospholipase C activity, 1-[6-[[17 beta-3- methoxyestra-1,3,5(10)-triene-17-yl]amino]hexyl]-1H-pyrrole-dione (U-73122) and an inactive analog 1-[6[[17 beta-3-methoxyestra-1,3,5(10)- triene-17-yl]amino]hexyl]2,5-pyrrolidine-dione (U-73343). U-73122 (10 microM) decreased GnRH-provoked (1 microM, 45 min) IP accumulation from 873 +/- 61 dpm to 365 +/- 50 dpm (basal accumulation also was decreased from 420 +/- 18 dpm to 207 +/- 16 dpm) while LH release was not inhibited (30.2 +/- 1.4% of cellular LH in control compared to 30.3 +/- 1.1% in U-73122 pretreated cells). GnRH provoked increased IP3 accumulation (123% of basal) after 15 sec of stimulation, IP2 accumulation (131% of basal) after 30 sec, and IP1 (121% of basal) after 1 min. Pretreatment with U-73122 blocked accumulation of IPs at these early timepoints. Sodium fluoride (NaF)-stimulated IP accumulation was also inhibited by U-73122 (from 1539 +/- 132 dpm to 414 +/- 21 dpm) while LH release increased from 22.9 +/- 1.4% total cellular LH to 28.0 +/- 2.2%. In contrast, GnRH- and NaF-stimulated IP accumulation were not significantly decreased in U-73343 pretreated cells (GnRH: 817 +/- 43 dpm compared to 873 +/- 61 dpm in control; NaF: 1133 +/- 74 dpm compared to 1539 +/- 132 dpm in control cells). Results of a perifusion study showed that U-73122 did not block the initial phase of GnRH-stimulated LH release or interfere with the development of desensitization to the releasing hormone. In addition, GnRH-stimulated intracellular Ca2+ fluctuations were similar in magnitude and duration in U-73122-pretreated compared to U-73343-pretreated cells. These results demonstrate that GnRH- as well as NaF-stimulated LH release can be uncoupled from IP production calling to question the role of IP3 as a second messenger for GnRH-stimulated LH release.
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PMID:Gonadotropin-releasing hormone-stimulated intracellular Ca2+ fluctuations and luteinizing hormone release can be uncoupled from inositol phosphate production. 159 51

Sodium fluoride (10 mM) caused a slow increase in the outputs of PGF-2 alpha, 6-keto-PGF-1 alpha and, to a lesser extent, PGE-2 from the Day-7 and Day-15 guinea-pig uterus superfused in vitro. This stimulatory action of sodium fluoride was not prevented by using calcium-free Krebs' solution. There was also a faster stimulation of 6-keto-PGF-1 alpha output from the Day-7 guinea-pig uterus produced by sodium fluoride, and this quicker response was abolished by using calcium-free Krebs' solution. TMB-8 (an intracellular calcium antagonist) inhibited the stimulatory action of sodium fluoride on the outputs of PGF-2 alpha, PGE-2 and 6-keto-PGF-1 alpha from the Day-7 guinea-pig uterus. W-7 and trifluoperazine (calmodulin antagonists) and neomycin (an inhibitor of phospholipase C) had no inhibitory effect on the increases in outputs of PGF-2 alpha, PGE-2 and 6-keto-PGF-1 alpha from the Day-7 guinea-pig uterus produced by sodium fluoride. These results indicate that sodium fluoride slowly stimulates uterine PGF-2 alpha, PGE-2 and 6-keto-PGF-1 alpha synthesis in the guinea-pig uterus by mobilizing intracellular calcium by a mechanism which apparently does not involve the activation of phospholipase C or the participation of calmodulin (or a related compound). The initial, faster stimulation of 6-keto-PGF-1 alpha synthesis in the Day-7 guinea-pig uterus by sodium fluoride is dependent upon extracellular calcium.
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PMID:Investigations into the mechanism by which sodium fluoride stimulates prostaglandin production in guinea-pig uterus. 240 99

Recently we have identified a novel choline and ethanolamine specific phospholipase C in myocardium and have hypothesized that this enzyme is responsible for the introduction of the vinyl ether linkage into plasmenylcholine by shuttling 1-O-alk-1'-enyl-2-acyl-sn-glycerol fragments from plasmenylethanolamine to plasmenylcholine (Wolf, R. A., and Gross, R. W. (1985) J. Biol. Chem. 260, 7295-7303). The present study demonstrates that rabbit myocardium contains endogenous 1-O-hexadec-1'-enyl-2-acyl-sn-glycerol (0.46 micrograms/g) and that these moieties are selectively utilized by myocardial choline phosphotransferase to generate plasmenylcholine. The apparent Michaelis constant of CDP-choline for microsomal choline phosphotransferase was 9 microM with a corresponding Vmax of 18 pmol/mg.min utilizing endogenous 1-O-alk-1'-enyl-2-acyl-sn-glycerol as substrate. The flux of CDP-choline into plasmenylcholine or phosphatidylcholine was similar despite the fact that the mass of endogenous 1,2-diacyl-sn-glycerol was over 20 times the mass of endogenous 1-O-alk-1'-enyl-2-acyl-sn-glycerol. Augmentation of endogenous 1-O-alk-1'-enyl-2-acyl-sn-glycerol content by pretreatment of myocardial microsomes with exogenous phospholipase C resulted in an 8-fold increase in plasmenylcholine synthesis. The results suggest that myocardial plasmenylcholine biosynthesis occurs by polar head group remodeling utilizing endogenous 1-O-alk-1'-enyl-2-acyl-sn-glycerol as a synthetic intermediate. Flux through this pathway is likely regulated by physiologic increments in endogenous 1-O-alk-1'-enyl-2-acyl-sn-glycerol content and cytosolic CDP-choline concentration.
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PMID:Identification of endogenous 1-O-alk-1'-enyl-2-acyl-sn-glycerol in myocardium and its effective utilization by choline phosphotransferase. 283 Feb 57

The role of G proteins in mediating adrenoceptor-prostacyclin synthesis coupling was investigated using the G protein activator, sodium fluoride. Sodium fluoride (NaF) stimulated in vitro rat aortic prostacyclin (PGI2) synthesis (EC50 = 5 x 10(-3) mol.l-1), an action inhibited completely by the presence of EDTA (10(-2) mol.l-1). The NaF-PGI2 dose-response curve was moved to the left by the presence of adrenaline, phorbol 12,13-dibutyrate (PDBU) and the Ca2+ ionophore A23187 in the incubation media. NaF-stimulated (5 x 10(-3) mol.l-1) PGI2 synthesis was inhibited by the Ca2+ channel blockers, verapamil and nifedipine, the protein kinase C inhibitor, H7, and lanthanum. Prazosin and yohimbine were without effect on NaF action, but partially inhibited adrenaline-potentiated NaF-stimulated PGI2 synthesis. Cyclic adenosine-3',5'-monophosphate (cAMP) and dibutyryl cAMP were without effect on de novo or NaF-, adrenaline-, PDBU- or A23187-stimulated PGI2 synthesis. Since fluoride is known to stimulate adenyl cyclase and phospholipase C, these data suggest that: (1) NaF stimulates in vitro rat aortic PGI2 synthesis by initiating Ca2+ influx; (2) this Ca2+ influx is mediated by protein kinase C, probably through G protein activation of phospholipase C and the generation of the protein kinase C activator, diacyl glycerol; and (3) adenyl cyclase and protein kinase A are not involved in NaF-stimulated PGI2 synthesis by the rat aorta.
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PMID:Fluoride stimulates in vitro vascular prostacyclin synthesis: interrelationship of G proteins and protein kinase C. 313 Nov 47

Sodium fluoride inhibited carbachol, 5-hydroxytryptamine and noradrenaline stimulated formation of inositol phosphates in rat cerebral cortex. For example, carbachol (1 mM) induced a 337% increase of inositol phosphates above basal in 30 min which was reduced to 69% in the presence of NaF (10 mM). The IC50 for NaF was approximately 1.5 mM and inhibition was mediated by a decrease in maxima of the carbachol dose response curve rather than a shift to the right. This inhibitory action was not mimicked by NaBr or NaI, or by agents which increase cAMP. Inhibition did not appear to result from a toxic action of NaF since it had no effect on the formation of inositol phosphates by high K+; moreover, in higher concentrations NaF stimulated phospholipase C activity. Since fluoride ions are known to activate G-proteins in the concentrations used in this study, these results may indicate the existence of a novel G-protein linked to receptor inhibition of phospholipase C.
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PMID:Fluoride inhibits agonist-induced formation of inositol phosphates in rat cortex. 313 93

Guinea pig tracheal epithelial cells in primary air/liquid interface culture (GPTE) and virally transformed human bronchial epithelial cells (BEAS-2B) were exposed to histamine at concentrations of 1 to 100 microM. At concentrations greater than 1 microM, histamine elicited a concentration-dependent increase in accumulation of inositol phosphates in both cell types, as assessed by anion exchange chromatography. The effects of histamine were most pronounced at 15 to 30 min and were attenuated by the H1-receptor antagonist, pyrilamine. The H2-receptor antagonist, ranitidine, was without effect. Sodium fluoride (25 mM), a non-receptor-associated activator of GTP binding (G) proteins, increased accumulation of inositol phosphates within GPTE and BEAS cells. In cells permeabilized with digitonin, the nonhydrolyzable GTP analog, guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S; 10 microM) increased inositol phosphate accumulation. This GTP gamma S-induced increase was attenuated by exposure to 500 microM guanosine-5'-O-(2-thiodiphosphate) (GDP beta S). Additionally, histamine-induced increases in inositol phosphate accumulation were potentiated by GTP gamma S and attenuated by GDP beta S. These data indicate involvement of a G protein in the response to histamine. Preincubation with pertussis toxin (100 ng/ml for 4 h) did not significantly affect the response, suggesting that the associated G protein was not pertussis toxin-sensitive. The presence of the phosphatidylinositol-specific phospholipase C (PI-PLC)-associated G protein, G alpha q/11, and the presence of mRNA for the Gq family, were ascertained by immunoblotting and Northern hybridization, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Histamine provokes turnover of inositol phospholipids in guinea pig and human airway epithelial cells via an H1-receptor/G protein-dependent mechanism. 769 21

Incubation of human keratinocytes with nanomolar concentrations of Staphylococcus aureus alpha-toxin leads to irreversible depletion of cellular ATP. The toxin forms hexamers in the target cell membranes, and rapid transmembrane flux of K+, Na+, and 86Rb+ is observed. Unexpectedly, pores formed in keratinocytes through application of low but lethal doses of alpha-toxin appeared to be considerably smaller than those formed in erythrocyte membranes. They permitted neither rapid influx of Ca2+ or propidium iodide, nor efflux of carboxyfluorescein. Larger pores allowing flux of all three markers did form when the toxin was applied at high concentrations. Flux of monovalent ions and reduction in cellular ATP levels evoked by low toxin doses correlated temporally with a fall in oxygen consumption, which was interpreted to reflect breakdown of mitochondrial respiration. The lethal event could not be thwarted by manipulating the extracellular K+ or Ca2+ concentrations. Realization that alpha-toxin may form very small pores in nucleated cells is important for future research on cellular toxin effects and membrane repair processes.
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PMID:Staphylococcal alpha-toxin kills human keratinocytes by permeabilizing the plasma membrane for monovalent ions. 822 71

Rat liver cells were homogenized and subsequently fractionated by a simplified method based on microfiltration, which proved to give a high recovery of membrane-bound phosphatidylinositol phospholipase C (PI-PLC) activity. The effects of insulin, acetylcholine (AC), epinephrine (EN) and bacterial phospholipase C (bPLC) on the PI-PLC activity were studied after in vitro treatment of isolated membranes or after in situ application in rat liver. A dose-dependent increase of membranous PI-PLC (up to 3-fold) and corresponding 36 to 72% decline of the cytosolic activity were established upon treatment with supraphysiological doses of insulin or with bPLC, respectively. AC induced a biphasic response with a maximal stimulation in the micromolar range. On the other hand EN promoted a slight but significant dose-dependent inhibition of PI-PLC in both cytosol and membranes. Sodium fluoride was also a potent inhibitor of the membrane-associated PI-PLC with an EC50 value of about 5 mM. The combined assay with NaF and EN revealed no additivity between their inhibitory effects, suggesting a common step in the mechanism(s) of inhibition caused by the two agents. The stimulatory effects of insulin and AC were partially reduced by soluble cytosolic factors, which still remain to be identified. When insulin and AC were applied in combination in the presence of cytosol, this resulted in a 56% inhibition of PI-PLC below the control level.
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PMID:Altered levels of phosphatidylinositol phospholipase C activity in rat liver cells in response to insulin, epinephrine, acetylcholine and bacterial phospholipase C. 838 21

The present study investigated transcellular signalling mechanism involved in thrombin-induced production of plasminogen activator inhibitor-1 (PAI-1) in cultured vascular baboon aortic smooth muscle cells (BASMC). Treatments with thrombin dose-dependently increased the steady state levels of PAI-1 mRNA and the generation of PAI-1 antigen from BASMC. Thrombin receptor-activating peptide mimicked the effect of thrombin on the generation of PAI-1. Sodium fluoride (1 mM) stimulated PAI-1 generation from BASMC. Pertussis toxin dose-dependently suppressed thrombin-induced increase of PAI-1 generation. Treatment with 5 mM neomycin, 10 microM U73122 or 1 microM calphostin C blocked thrombin-induced PAI-1 generation. Phorbol myristate acetate at 10 nM for 3 h strongly stimulated the generation of PAI-1 from BASMC. Forskolin (100 microM) or 8-bromo-cAMP (100 microM) suppressed thrombin-induced PAI-1 generation. The responses of quiescent BASMC to thrombin or the inhibitors on PAI-1 generation were comparable to that of growing cells. The results of the present study suggest that pertussis toxin-sensitive G proteins and a phospholipase C are involved in thrombin-induced generation of PAI-1 in BASMC, which may transmit signals from occupied thrombin receptor to protein kinase C and thereby increase the generation of PAI-1. Elevated levels of intracellular cAMP may negatively regulate the generation of PAI-1 from vascular SMC.
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PMID:G proteins and phospholipase C mediate thrombin-induced generation of plasminogen activator inhibitor-1 from vascular smooth muscle cells. 916 40

We compared agonist-evoked responses in the perfused mesenteric vascular bed (MVB) of streptozotocin (STZ) diabetic Sprague-Dawley rats 2 and 14 weeks after induction of diabetes. Endothelin-1 (ET-1)-, methoxamine (MTX)-, and KCl-evoked vasoconstrictor responses were unchanged in 2-week-old diabetic rats. In contrast, both the sensitivity (P < 0.01) and the maximal vasoconstrictor responses (P < 0.05) to ET-1 were attenuated in 14-week-old diabetic rats, whereas endothelin plasma levels were increased (P < 0.05). Although no differences were observed in responses to KCl in either the 2- or 14-week-old diabetic groups, MTX-evoked maximal responses were attenuated in the 14-week-old group (P < 0.01). Changes in agonist-evoked responses in the 14-week-old diabetic group were unaffected by the protein kinase C (PKC) inhibitor, staurosporine, the phospholipase C (PLC) inhibitor, U73122, the calcium channel blocker, nifedipine, the calcium pump inhibitor, cyclopiazonic acid (CPA), or by endothelial denudation. Sodium fluoride (NaF), an activator of guanosine triphosphate binding proteins (G proteins) normalized the responses in the 14-week-old diabetic group. These data suggest that advanced stages of STZ are associated with alterations in G protein receptor coupling and/or activity leading to the attenuation of responses to vasoconstrictor agonists.
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PMID:Attenuated agonist evoked vasoconstrictor responses in the perfused mesenteric vascular bed of streptozotocin diabetic rats. 1168 1


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