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)

An investigation was undertaken of the mechanism by which oxyhemoglobin and its analog methemoglobin might cause cerebrovascular spasm. The effect of these compounds on the levels of intracellular inositol triphosphate and calcium in cultured primate cerebrovascular smooth-muscle cells and the contractile action of oxyhemoglobin on isolated rings of primate cerebral arteries were also examined. Oxyhemoglobin, but not methemoglobin, produces a transient but highly significant increase in the intracellular levels of inositol triphosphate. Intracellular calcium levels in these cells are increased by thrombin, aluminum tetrafluoride, and oxyhemoglobin, and the sustained elevation in intracellular calcium is prevented by ethyleneglycol tetra-acetic acid and the phospholipase C inhibitor neomycin. Removal of the oxyhemoglobin after as long as 48 hours' incubation with this compound allowed cells to rapidly reduce their intracellular calcium levels to near normal. Oxyhemoglobin produced contractions of isolated rings of both normal and spastic cerebral arteries, although the response of spastic vessels was significantly smaller. This effect was inhibited by neomycin. The addition of neomycin relaxed arteries that were contracted with oxyhemoglobin, 5-hydroxytryptamine, or potassium chloride. It is thus likely that activation of phospholipase C is a critical step in the development of vasospasm, but the transient nature of the response to inositol triphosphate suggests that the sustained contraction may arise from other phospholipase C-dependent mechanisms.
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PMID:Intracellular mechanisms involved in the responses of cerebrovascular smooth-muscle cells to hemoglobin. 828 65

In order to investigate a possible G-protein-mediated activation of phospholipase D (PLD) and its relationship to the activation of phosphoinositide-specific phospholipase C (PI-PLC), we measured the effects of aluminium fluoride and carbachol on choline release, the PLD-specific transphosphatidylation reaction (generation of phosphatidylpropanol) and the formation of inositol phosphates in rat hippocampal slices. Aluminium fluoride markedly enhanced the formation of choline and phosphatidylpropanol but failed to increase the formation of inositol phosphates. In contrast, the muscarinic agonist carbachol strongly stimulated PI-PLC but failed to activate PLD. We conclude that PLD in hippocampal slices is activated by a G-protein independently of phosphoinositide hydrolysis.
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PMID:Phospholipase C and phospholipase D are independently activated in rat hippocampal slices. 830 85

15(S)-Hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid (15-HETE) exerted a time- and concentration-dependent inhibition of superoxide anion (O2-) production and exocytosis of both azurophil and specific granule constituents from human polymorphonuclear neutrophils (PMN) stimulated with the receptor-specific agonists, N-formylmethionylleucylphenylalanine (FMLP), platelet-activating factor, and leukotriene B4, but not that elicited by phorbol 12-myristate 13-acetate. 15-HETE did not alter the binding of FMLP to its specific receptors on PMN but, rather, appeared to interfere with a subsequent process in signal transduction. Receptor-coupled production of inositol 1,4,5-trisphosphate (InsP3) and increases in cytosolic free calcium elicited with FMLP, platelet-activating factor, and leukotriene B4 were suppressed by 15-HETE. 15-HETE did not, however, inhibit the mobilization of 45Ca from intracellular stores elicited by the addition of InsP3 to permeabilized PMN. 15-HETE suppressed O2- production and increases in intracellular [Ca2+] induced when cell-surface receptors were bypassed and the PMN were activated directly by the guanine nucleotide-binding protein (G protein) activators aluminum fluoride (AlF4-) and mastoparan. 15-HETE, however, did not perturb all G protein functions because cAMP production in FMLP-activated PMN was essentially unaffected by 15-HETE. These data support the proposition that 15-HETE modulates receptor-triggered activation of PMN either by uncoupling G protein stimulation of phospholipase C or by directly inhibiting phospholipase C, thus inhibiting the InsP3-dependent rise in intracellular [Ca2+] that is prerequisite for PMN responsiveness to receptor agonists.
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PMID:Transmembrane signaling in human polymorphonuclear neutrophils: 15(S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid modulates receptor agonist-triggered cell activation. 839 15

We have shown previously that aluminum chloride (AlCl3, 10-500 microM) inhibits hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphatidylinositol-specific phospholipase C (PI-PLC) in a concentration-dependent manner. In the present study, we characterize further the effects of aluminum on PI-PLC. A comparison of different brain regions and liver revealed varying basal PI-PLC specific activities, as well as differential susceptibility to inhibition by 100 microM AlCl3. The hippocampus had the highest specific activity of PI-PLC, followed by striatum, frontal cortex, cerebellum, and liver. PI-PLC inhibition by 100 microM AlCl3 was greatest in the liver, followed by cerebellum, hippocampus, cortex, and striatum. Moreover, 100 microM AlCl3 or aluminum lactate (Al (lac)) were similarly effective at inhibiting PI-PLC activity in rat cortical tissue. Addition of AlCl3 (100 microM) decreased PI-PLC activity at CaCl2 concentrations ranging from 0 to 2 mM; however, AlCl3 did not affect the shape of the calcium concentration curve, suggesting that aluminum does not inhibit PI-PLC activity by interference with the cofactor, calcium. AlCl3 (100 microM) did inhibit rat cortical PI-PLC hydrolysis of PIP2 in a competitive manner. These results demonstrate some regional/tissue differences in PI-PLC activity and its sensitivity to aluminum, and effects of AlCl3 and Al(lac) consistent with the effects previously noted in PI turnover in brain slices. Furthermore, our results suggest that competitive inhibition of PLC-mediated PIP2 hydrolysis by aluminum is a potential mechanism by which aluminum may cause the disruptions phosphoinositide signaling which have been reported following in vivo and in vitro exposure.
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PMID:Inhibition of rat brain phosphatidylinositol-specific phospholipase C by aluminum: regional differences, interactions with aluminum salts, and mechanisms. 856 Apr 64

The activation of GTP-binding proteins (G-proteins) by sodium fluoride + aluminum (AlF4-) was shown in several cell free systems. In the intact cell, NaF +/- aluminum was shown to activate various signal transduction pathways and indirect evidence is in line with effector mechanisms involving regulation of G-protein activity. We have explored the effect of NaF on several components of signal transduction pathways in macrophages. NaF was shown to reduce intracellular ATP levels and to suppress agonist-induced protein tyrosine phosphorylation and reactive oxygen species formation. NaF led to in situ activation of nitrogen activated protein kinase, phospholipase A2 and PtdIns-phospholipase C. Addition of AlCl(3) or deferoxamine, a chelator of aluminum, had little or no effect on NaF mediated enzyme activation. The results suggest that at least some of the pleiotropic effects of NaF in intact cells may not be mediated by G-protein activation but rather by depletion of ATP which is essential for protein phosphorylation reactions.
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PMID:A pleiotropic effect of fluoride on signal transduction in macrophages: is it mediated by GPT-binding proteins? 856 81

Deoxycorticosterone-salt (DOCA-salt) hypertension is characterized by elevated vasoconstriction to agonists that stimulate G protein-mediated activation of phospholipase C. However, the mechanisms responsible for the augmented responsiveness are unknown. This study tested the hypothesis that this augmented vascular responsiveness is due to elevated content of G(alpha)q, the G protein alpha-subunit that activates phospholipase C. Thoracic aortae from DOCA-salt hypertensive rats (systolic blood pressure 183 +/- 7 mm Hg) and normotensive controls (systolic blood pressure 115 +/- 2 mm Hg) were homogenized and G protein content determined. Western analysis revealed that G(alpha)i content was decreased in DOCA compared with control rats (1364 +/- 196 versus 2343 +/- 188 densitometry units, P < or = .05) with no differences observed for G(alpha)q or G(alpha)s. In addition, contractile responses in denuded femoral artery strips revealed a significant decrease in EC50 values in DOCA arteries to all of the agonists examined: aluminum fluoride (DOCA = 1.42, control = 2.34 mmol/L), mastoparan (DOCA = 0.51, control = 35 micromol/L), phenylephrine (DOCA = 0.08, control = 0.53 micromol/L), and serotonin (DOCA = 0.014, control = 0.04 micromol/L, EC20 values). Finally, arteries from DOCA rats contracted with aluminum fluoride had increased sensitivity to G protein antagonists but not to a phospholipase C inhibitor. The enhanced contractile responsiveness in the DOCA arteries may be mediated in part through decreased G(alpha)i levels. However, it is not caused by increased concentrations of G(alpha)q in the cell membrane or by increased phospholipase C sensitivity, and the increased constrictor response to G protein stimulators of phospholipase C appears to depend primarily on increased G protein sensitivity.
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PMID:Increased responsiveness and decreased expression of G proteins in deoxycorticosterone hypertension. 861 34

Cardiac Na+,Ca2+ exchange is activated by a mechanism that requires hydrolysis of adenosine triphosphate (ATP) but is not mediated by protein kinases. In giant cardiac membrane patches, ATP acted to generate phosphatidylinositol-4,5-bisphosphate (PIP2) from phosphatidylinositol (PI). The action of ATP was abolished by a PI-specific phospholipase C (PLC) and recovered after addition of exogenous PI; it was reversed by a PIP2-specific PLC; and it was mimicked by exogenous PIP2. High concentrations of free Ca2+ (5 to 20 microM) accelerated reversal of the ATP effect, and PLC activity in myocyte membranes was activated with a similar Ca2+ dependence. Aluminum reversed the ATP effect by binding with high affinity to PIP2. ATP-inhibited potassium channels (KATP) were also sensitive to PIP2, whereas Na+,K+ pumps and Na+ channels were not. Thus, PIP2 may be an important regulator of both ion transporters and channels.
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PMID:Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2. 868 80

Extracellular cations have paradoxical trophic and toxic effects on osteoblast function. In an effort to explain these divergent actions, we investigated in MC3T3-E1 osteoblasts if polyvalent cations differentially modulate the agonist-stimulated cyclic adenosine monophosphate (cAMP) pathway, an important regulator of osteoblastic function. We found that a panel of cations, including gadolinium, aluminum, calcium, and neomycin, inhibited prostaglandin E1 (PGE)-stimulated cAMP accumulation but paradoxically potentiated parathyroid hormone (PTH)-stimulated cAMP production. In contrast, these cations had no effect on forskolin- or cholera toxin-induced increases in cAMP, suggesting actions proximal to adenylate cyclase and possible modulation of receptor interactions with G proteins. Phorbol 12-myristate 13-acetated (PMA) mimicked the effects of cations on PGE1- and PTH-stimulated cAMP accumulation in MC3T3-E1 cells, respectively, diminishing and augmenting the responses. Moreover, down-regulation of protein kinase C (PKC) by overnight treatment with PMA prevented gadolinium (Gd3+) from attenuating PGE1- and enhancing PTH-stimulated cAMP production, indicating involvement of PKC-dependent pathways. Cations, however, activated signal transduction pathways not coupled to phosphatidylinositol-specific phospholipase C (PI-PLC), since there was no corresponding increase in inositol phosphate formation or intracellular calcium concentrations. In addition, pertussis toxin treatment failed to prevent Gd(3+)-mediated suppression of PGE1-stimulated cAMP, suggesting actions independent of Gm. Thus, polyvalent cations may either stimulate or inhibit hormone-mediated cAMP accumulation in osteoblasts. These differential actions provide a potential explanation for the paradoxical trophic and toxic effects of cations on osteoblast function that occur in vivo under different hormonal conditions.
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PMID:Differential regulation of receptor-stimulated cyclic adenosine monophosphate production by polyvalent cations in MC3T3-E1 osteoblasts. 872 76

We assessed the sensitivity of phospholipase D (PLD) activity in vascular smooth muscle to cytosolic Ca2+ by increasing cytosolic Ca2+ levels independently of agonist stimulation. When rat tail artery was preloaded with the Ca2+ indicator fluo 3 pentaacetoxymethyl ester, the addition of high extracellular K+, caffeine, or norepinephrine rapidly enhanced cytosolic Ca2+ levels. Neither increased extracellular K+ nor caffeine addition increased phosphatidylethanol production, indicating that cytosolic Ca2+ elevation alone did not stimulate PLD. In contrast, norepinephrine stimulated phosphatidylethanol production in this tissue. In strips of tail artery permeabilized with alpha-toxin and incubated in solutions containing free Ca2+ concentrations observed during physiological stimulation (pCa 6.4), PLD was not stimulated, whereas incubation with guanosine 5'-O-(3-thiotriphosphate) at pCa 7.0 activated this enzyme. Aluminum fluoride (AlF4-) stimulated PLD, and this activity was insensitive to pertussis toxin after stimulation by either norepinephrine or AlF4-. These results indicate that PLD in vascular smooth muscle is activated by norepinephrine via stimulation of a pertussis toxin-insensitive G protein and not via an increase in intracellular Ca2+ levels.
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PMID:Phospholipase D is activated by G protein and not by calcium ions in vascular smooth muscle. 878 Feb

The effect of morphine on amylase secretion was studied in isolated rat parotid acinar cells. It was found that aluminum fluoride (AlCl3/NaF) and dibutyryl-cyclic AMP but not by cyclic AMP, enhanced amylase secretion. Cyclic AMP was effective in enhancing secretion following permeabilization of cells with alpha-toxin. Following treatment of cells with alpha-toxin, both GTP and GTP-gamma-S also enhanced secretion. Morphine reduced AlCl3/NaF- or GTP-induced secretion of amylase, but was without effect on GTP-gamma-S-induced secretion. Photoaffinity labeling by the use of [32P] 4-azidoanilido GTP revealed its incorporation into 43 kDa and 31 kDa proteins. Incorporation was further enhanced with AlCl3/NaF. Morphine reduced labeling of the 43 kDa protein. Immunoblot analysis identified the 43 kDa GTP binding protein as Gs. When [gamma 32P] GTP was preloaded into permeabilized acinar cells and its hydrolysis measured, morphine stimulated and AlCl3/NaF inhibited GTPase activity. These results suggested the involvement of Gs in secretion of amylase. Furthermore, morphine reduced secretion of amylase by stimulating GTPase activity and by reducing the incorporation of GTP into Gs.
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PMID:Effect of morphine on secretion of amylase from isolated parotid acini. 893 8


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