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)

Inositol 1,4,5-triphosphate (IP3) is generated as a second messenger in many diverse cellular signalling pathways. In general these signalling pathways activate a membrane-bound phospholipase C, which cleaves the phospholipid phosphatidylinositol bisphosphate to generate IP3 and diacylglycerol. IP3 binds to a specific intracellular receptor, which is a membrane protein and a ligand-gated Ca2+ channel, that causes Ca2+ release from intracellular stores. The inositol 1,4,5-triphosphate receptor (IP3R) is thus an integral part of the IP3 signalling pathway and can be used as a marker to identify biological processes that use IP3 as a second messenger. We have used an affinity-purified antibody, directed against a bacterial fusion protein and containing 339 amino acids of the Drosophila IP3R, to detect this protein in adult heads and during embryonic and pupal development. Our results suggest that in Drosophila the IP3 signalling pathway is used during muscle development, primarily when myoblasts undergo rapid multiplication, in both embryos and pupae. In adults, IP3 is probably a second messenger in more than one sensory transduction pathway, as well as in other as yet undefined brain and muscle functions.
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PMID:The inositol 1,4,5-triphosphate receptor expression in Drosophila suggests a role for IP3 signalling in muscle development and adult chemosensory functions. 755 37

Inositol phospholipids (IPL) from epimastigote forms of Trypanosoma cruzi have been investigated by metabolic labelling with [3H]palmitic acid and by GLC-MS analysis of the lipids obtained from non-labelled parasites. The IPL fraction was separated into phosphatidylinositol (PI) and inositol-phosphoceramide subfractions, the latter accounting for 80-85% of the total IPL. The neutral lipids released from the IPLs by PI-specific phospholipase C (PI-PLC) from Bacillus thuringiensis were analysed by silica-gel and reverse-phase TLC for the radioactive lipids and by GLC-MS for the non-radioactive samples. Ceramides containing dihydrosphingosine and sphingosine with C16:0 and C18:0 fatty acids were identified. The main component in the [3H]palmitic acid-labelled ceramides was palmitoyldihydrospingosine, while in the non-labelled sample the ceramides contained mainly sphingosine. This could reflect partial uptake of phospholipid from the medium. The PI contain both alkylacyl- and diacyl-glycerol lipids, with the ether lipid being more abundant. The latter was identified as 1-O-hexadecylglycerol esterified by C18:2 and C18:1 fatty acids. Interestingly, the same lipid had been identified in the anchor of the 1G7 glycoprotein of T. cruzi metacyclic forms.
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PMID:Structural analysis of inositol phospholipids from Trypanosoma cruzi epimastigote forms. 764 54

The PTH receptor has been cloned and shown to activate both adenylate cyclase and phospholipase C. Evidence exists that both signaling pathways are important for mediating the net physiological effects of this hormone on bone remodeling. We have shown previously that UMR-106 osteoblastic sarcoma cells express two calcium-signaling P2 purinergic receptors, a P2U and a unique P2T receptor. Neither receptor modulates PTH receptor-mediated activation of adenylate cyclase. We now report that stimulation of either P2 receptor will, however, potentiate the magnitude of the calcium signal observed after subsequent addition of human (h) PTH-(1-34) to fluo-3-loaded UMR-106 cells. Results from experiments with staurosporine and phorbol 12-myristate 13-acetate argue against a role for protein kinase C as a mediator of this potentiating effect of P2 receptor ligands. The P2 receptor-mediated intracellular calcium elevation itself cannot account for the potentiating mechanism, because addition of ionomycin will not replicate the effect of P2 receptor ligands on hPTH-(1-34) signaling. Addition of EGTA after exposure to P2 ligands does not prevent the potentiation of hPTH-(1-34), indicating that P2 ligands potentiate the release of intracellular calcium after PTH receptor stimulation. Inositol trisphosphate production is potentiated in response to hPTH-(1-34) after first priming [3H]inositol-labeled cells with a P2 agonist. We conclude that UMR-106 cells express PTH receptors that are capable of activating adenylate cyclase, but may be unable to activate phospholipase C until cells receive a signal as a consequence of P2 receptor activation. The nature of the signal is unclear, but appears not to be mediated by either calcium or protein kinase C.
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PMID:P2 purinergic receptors potentiate parathyroid hormone receptor-mediated increases in intracellular calcium and inositol trisphosphate in UMR-106 rat osteoblasts. 766 69

[3H]Myristic acid prelabeled LA-N-2 cells were exposed to varying concentrations of amyloid beta protein (25-35), from 20 to 250 micrograms/ml, and the activation of phospholipases A and D estimated. A progressive increase in phosphatidylethanol formation, a measure of phospholipase D activity, and of free fatty acid release, a measure of phospholipase A activity, was observed over a time-course of 60 min. [3H]Inositol prelabeled LA-N-2 cells were exposed to varying concentrations of A beta P, from 20 to 125 micrograms/ml, and phospholipase C activation was measured. There was an increased release of inositol phosphates in the presence of amyloid beta protein as a function of incubation time. The effects of adrenergic, metabotropic amino acid and bombesin antagonists on the A beta P mediated stimulation of phospholipase C activity was investigated. Propranolol, a beta adrenergic antagonist, 7-chloro-kynurenic acid, a metabotropic amino acid antagonist, and [Tyr4-D-Phe12]bombesin, a bombesin antagonist, blunted the A beta P stimulation of phospholipase C activity in [3H]inositol prelabeled LA-N-2 cells. This suggests that amyloid beta protein activation of phospholipase C may be receptor mediated. The phospholipase C inhibitor U 71322 prevented the activation of phospholipase C by A beta P. However, this activation was not effected by tocopherol, propylgallate, or vitamin C.
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PMID:Amyloid beta protein (25-35) stimulation of phospholipases A, C and D activities of LA-N-2 cells. 778 63

Secretion of insulin from beta cells of the pancreatic islets is regulated by glucose, its anaerobic metabolism and its metabolites. The phospholipids of the cell membrane the phosphoinositides are broken down by the activation of the enzyme phospholipase C either through the occupation of the receptor by an agonist or through the metabolism of glucose in the anaerobic glycolytic pathway. The hydrolysis of the phosphotidyl inositide-bisphosphate yields to the generation of Inositol 1, 4, 5-trisphosphate and diacylglycerol. Ins-1, 4, 5-P3 increases the intracellular Ca2+ by releasing the sequestered Ca2+ in the endoplasmic reticulum and diacylglycerol activates the enzyme protein kinase C.
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PMID:Phosphoinositide metabolism and insulin secretion. 780 52

A role for phospholipase C hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] as a mechanism of alpha 2-adrenergic signal transduction in rabbit tracheal epithelial cells (tracheocytes) was investigated in isolated cells grown in in vitro culture and prelabeled with myo-[3H]inositol (3 microCi/ml) for 72 h. Breakdown of polyphosphoinositides was measured by using thin-layer chromatography to detect phosphatidylinositol, phosphatidylinositol 4-phosphate [PtdIns(4)P], and PtdIns(4,5)P2. Inositol phosphates were separated by ion-exchange column chromatography. The endogenous catecholamine l-epinephrine and alpha 2-adrenergic agonists clonidine and 1-(2,6-dichlorobenzylideneamino)guanidine (guanabenz) produced a rapid transient accumulation of inositol trisphosphate and inositol 4,5-bisphosphate and breakdown of [PtdIns(4)P] and PtdIns(4,5)P2. The alpha 2-adrenergic effects were not blocked by the beta-adrenergic antagonist DL-propranolol or by the alpha 1-adrenergic antagonists prazosin and methylurapidil but were inhibited by pertussis toxin and blocked by yohimbine, an alpha 2-adrenergic antagonist. The 50% effective concentration for guanabenz-stimulated inositol trisphosphate generation was right shifted from 0.3 to 0.9 microM by yohimbine. The results provide the first demonstration of alpha 2A-adrenergic activation of pertussis toxin-sensitive PtdIns(4,5)P2-dependent phospholipase C in mammalian tracheocytes. The findings are consistent with previous observations on alpha 2A-adrenergic-mediated activation of NaCl cotransport in these cells.
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PMID:Activation of PtdIns(4,5)P2-sensitive phospholipase C in rabbit tracheal epithelial cells. 790 69

Inositol phospholipid-specific phospholipase C (PLC) is involved in several signaling pathways leading to cellular growth and differentiation. Our previous studies reported the induction of DNA synthesis in quiescent NIH 3T3 cells after microinjection of PLC and the inhibition of serum- or Ras-stimulated DNA synthesis by a mixture of monoclonal antibodies to PLC-gamma 1. In the course of our investigation of anti-PLC-gamma 1 monoclonal antibodies, we found that each antibody exerts different inhibitory effects on the phosphatidylinositol-hydrolyzing activity of PLC-gamma 1 and that the inhibition of enzymatic activity does not correlate with the inhibition of DNA synthesis observed in the microinjection assay. PLC-gamma 1 with defective enzymatic activity was synthesized by substituting phenylalanine for histidine within the PLC-gamma 1 catalytic domain at amino acids 335 and 380, and mutant enzymes were expressed using a vaccinia expression system. The mutant enzymes were purified and microinjected into quiescent NIH 3T3 cells to evaluate their mitogenic activity. A moderate induction of DNA synthesis occurred after injection of mutant PLC-gamma 1. This mitogenic activity was inhibited by an antibody (alpha E 8-4) that does not significantly inhibit PLC-gamma 1 enzyme activity, which indicates that something else has to be inhibited. Furthermore, the partial induction of DNA synthesis observed with mutant PLC-gamma 1 was increased to levels seen with wild-type PLC-gamma 1 by coinjection of mutant PLC-gamma 1 with two second messengers, diacylglycerol and inositol trisphosphate. These results suggest that the mitogenic activity of PLC-gamma 1 does not exclusively result from the enzymatic activity of the lipase and that another activity inherent to the PLC-gamma 1 molecule can also induce DNA synthesis in quiescent cells.
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PMID:Phospholipase C-gamma 1 can induce DNA synthesis by a mechanism independent of its lipase activity. 802 19

Thrombin is by far the most potent platelet agonist. Potentially this reflects multiple intracellular processes involved in transmitting the activation signal from the initial contact with a receptor, or binding site, to the final platelet response. Platelet membranes have two putative receptors: the high affinity glycoprotein Ib, whose function remains to be clarified, and the moderate affinity autoproteolytic receptor. The autoproteolytic receptor is a member of a family of receptors, with seven transmembrane domains, which interact with GTP-binding proteins. Distal to the membrane, several forms of phospholipase C are activated and roles for both heterotrimeric and low molecular mass GTP-binding proteins have been presented. Phospholipase C acts on inositol phospholipids to generate inositol trisphosphate and diacylglycerol, both of which function as second messengers in thrombin-induced platelet activation. Inositol trisphosphate mobilizes internal calcium stores and this is accompanied, and enhanced, by an influx of calcium from the external milieu. Diacylglycerol and calcium both serve to regulate the activity of multiple protein kinases which, in turn, mediate the phosphorylated state of numerous proteins. Phosphorylation can occur on serine, threonine or tyrosine residues of target proteins and the phosphorylated state of these proteins determines the final activation of the platelet.
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PMID:Post-receptor events associated with thrombin-induced platelet activation. 814 90

Intracellular Ca2+ responses to extracellular matrix molecules were studied in suspensions of pancreatic acinar cells loaded with Fura-2. Collagen type I, laminin, fibrinogen and fibronectin were unable to raise cytosolic free Ca2+ concentration ([Ca2+]i), whereas collagen type IV, at concentrations from 5 to 50 micrograms/ml, significantly increased it. The effect of collagen type IV was not due to possible contamination with type-I transforming growth factor beta or plasminogen, as neither of these agents was able to increase [Ca2+]i. Using highly specific mass assays, concentrations of inositol lipids, 1,2-diacylglycerol (DAG) and Ins(1,4,5) P3 were measured in pancreatic acinar cells stimulated with collagen type IV. A decrease in the concentrations of PtdIns(4,5) P2 and PtdIns4 P with a concomitant increase in the concentrations of DAG and InsP3 mass were observed, showing that collagen type IV increases [Ca2+]i by activation of phospholipase C. The observed [Ca2+]i signals had two components, the first resulting from Ca2+ release from the intracellular stores, and the second resulting from Ca2+ flux from the extracellular medium through the verapamil-insensitive channels. A tyrosine kinase inhibitor (tyrphostine) was able to block inositol lipid signalling caused by collagen type IV, which together with the insensitivity of this pathway to cholera toxin and pertussis toxin or to preactivation of protein kinase C, the longer duration of the increase in [Ca2+]i and a longer lag period needed for observation of increases in DAG and InsP3 concentration with collagen type IV than with carbachol (50 mM) suggest that activation of phospholipase C by collagen type IV is caused by tyrosine kinase activation. Inositol lipid signalling and increases in [Ca2+]i were also observed with Arg-Gly-Asp (RGD)-containing peptide but not with Arg-Asp-Gly (RDG)-containing peptide. Collagen type IV and RGD-containing peptide, but not carbachol, competed in increasing [Ca2+]i and DAG concentration, suggesting that the binding site of collagen type IV responsible for phospholipase C activation contains the RGD sequence. Together the present results suggest that, in pancreatic acinar cells, RGD sequence(s) within collagen type IV molecules cause activation of tyrosine kinase, probably through one of the integrin receptors, which then stimulates phospholipase C and increases [Ca2+]i.
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PMID:Collagen type IV stimulates an increase in intracellular Ca2+ in pancreatic acinar cells via activation of phospholipase C. 819 49

Phospholipase C-mediated release of inositol trisphosphate, followed by an increase in free intracellular calcium, is an important signal transduction pathway for several membrane receptors. In the present investigation, the coupling of various receptors to phospholipase C was studied in the human keratinocyte line HaCaT. Inositol trisphosphate formation was determined by anion-exchange chromatography, and the release of intracellular calcium was analysed with the fluorescence probe Fura-2 AM. Activation of HaCaT keratinocytes with bradykinin resulted in a time- and dose-dependent release of inositol trisphosphate and intracellular calcium, with an EC50 value of 50 nM for bradykinin-induced inositol trisphosphate formation. The mediators and cytokines IL-1, IL-4, IL-6, IL-8, EGF and TGF alpha, as well as bombesin, prolactin, carbachol, substance P and retinoic acid, did not activate this pathway. The inability of the mediators examined to activate phospholipase C may be due to lack of the respective cognate receptors or to the use of other signal transduction pathways.
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PMID:Inositol phosphate formation and release of intracellular free calcium by bradykinin in HaCaT keratinocytes. 830 79


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