Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine which subtype of adenosine receptor mediates the potentiating effect of 2-chloroadenosine on the noradrenaline-induced inositol-phosphate formation, we used the monoclonal anti-idiotypic antibody AA1 that acts as an 'internal image' of adenosine and specifically recognizes the A1 adenosine receptor. In cultured mouse striatal astrocytes, AA1 increased the noradrenaline-evoked inositol phosphate (IP) accumulation, thus demonstrating a biological activity of an anti-idiotypic antibody. This effect was inhibited by PACPX, a selective A1 antagonist. Inhibitors of phospholipase A2 activity prevented the potentiation. These results establish the involvement of A1 adenosine receptors in the modulation of phospholipase C activity.
Neurosci Lett 1992 Sep 28
PMID:A monoclonal anti-idiotypic 'internal image' antibody that recognizes the A1 adenosine receptor potentiates the alpha 1-adrenergic activation of phospholipase C in primary cultures of mouse striatal astrocytes. 133 41

The activity of a phosphodiesterase of the phospholipase C (PLC) type and factors influencing its activity were studied in ascites tumor cells. The enzyme confined to the 12,000 x g particulate fraction hydrolyses inositol phospholipids, with preference for phosphatidylinositol 4-phosphate (PtdIns(4)P) over phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), exhibiting maximum values of 61 and 15 nmol/min per mg protein, respectively, at a pH optimum of 5.5. The phosphodiesterase, which is strongly Ca2+ dependent with optimal free Ca2+ concentrations between 20 and 100 nM for both substrates, is almost completely inhibited (93-95%) in the presence of 2 mM EGTA. Only the PLC acting on PtdIns(4,5)P2 is significantly activated in the presence of 6-60 microM GTP gamma S. The low extent of enzymatic activity in the presence of 5 mM MgCl2 or chelating agents is suggestive of inositolphosphatase activity which is supported by the determination of small amounts of myo-inositol during HPLC analyses. Both dioleoylglycerol (DAG) and the membrane-permeable 1-oleoyl-2-acetyl-sn-glycerol (OAG) inhibit PLC activity, exhibiting IC50 values of 5 microM with PtdIns(4)P and approx. 10 microM with PtdIns(4,5)P2 as substrate and maximum inhibition up to 60% (DAG) and 80% (OAG). These data are indicative of a mechanism of direct negative feedback regulation of the enzyme by diglycerides which may explain the observed long-term effects of OAG on PLC activity in cell culture experiments.
J Lipid Mediat 1992 Sep
PMID:Ca2+ and partly GTP gamma S-dependent particulate phospholipase C hydrolyzing phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate is inhibited by diacyl(acyl-acetyl) glycerols. 133 19

Induction of polyphosphoinositide hydrolysis in cardiac tissue by IgG from chagasic mice was assayed. BALB/c mice auricles were labelled with myo-[3H]inositol precursor and inositol phosphate production in the presence or absence of chagasic IgG and the corresponding F(ab')2 was measured. Both chagasic IgG and F(ab')2 but not the normal forms specifically increased phosphoinositide turnover. This increment was blocked by muscarinic cholinergic antagonists and to an even greater extent by the phospholipase C inhibitor NCDC. Moreover, calcium channel blocking agents such as diltiazem, verapamil and D-600 also exerted an inhibitory action. A muscarinic cholinergic agonist, carbachol, and the ionophore A-23187, mimicked the action of the chagasic IgG upon phosphoinositide turnover. It is concluded that murine chagasic IgG and its F(ab')2 fragments result in stimulation of phospholipase C-mediated phosphoinositide hydrolysis through the interaction with muscarinic cholinergic receptors requiring the cytosolic calcium concentration to be raised.
J Lipid Mediat 1992 Sep
PMID:Chagasic IgG stimulates phosphoinositide hydrolysis via neurotransmitter receptor activation: role of calcium. 133 20

Our previous study of natural autoantibodies showed that anti-lymphocyte antibodies are frequently produced by perinatal B cells from normal strains of mice. One-third of these monoclonal antibodies (mAb) recognized similar epitopes on the surface of thymocytes. In the present report, we have characterized the molecule recognized by three of these mAb (D10, G7, 22). These mAb identified a 100-kDa protein (p100) on the surface of thymocytes. This protein resolved into 70-kDa polypeptide chains under reducing conditions. Inhibition experiments as well as antibody immunoprecipitations in the presence of mild detergents revealed non-covalent association of the p100 with Thy-1 and ThB. A similar multimolecular complex was identified following chemical cross-linking of thymocyte surface proteins. Analysis of several Thy-1-defective mutant cells lines, and thymocytes treated with phosphatidylinositol-specific phospholipase C (PI-PLC) showed that the expression of p100 was strongly influenced by Thy-1 molecule. The p100 was resistant to PI-PLC treatment and was not released into the supernatant as was the case for Thy-1 and ThB molecules. These data lead us to propose that the p100 is a transmembrane protein, the expression of which in the plasma membrane is dependent on the association or presence of Thy-1 molecule.
Eur J Immunol 1992 Sep
PMID:Identification of a surface protein (p100) associated with two glycosyl-phosphatidylinositol-linked molecules (Thy-1 and ThB) by natural anti-lymphocyte autoantibodies. 135 32

We have characterized a G-protein-coupled glutamate receptor in primary cultures of striatal neurons. Glutamate, quisqualate, or trans-1-aminocyclopentane-1,3-dicarboxylate inhibited by 30-40% either forskolin-stimulated cAMP production in intact cells or forskolin plus vasoactive intestinal peptide-activated adenylyl cyclase assayed in neuronal membrane preparations. These inhibitory effects were suppressed after treatment of striatal neurons with Bordetella pertussis toxin, suggesting the involvement of a heterotrimeric guanine nucleotide-binding protein (G protein) of the G(i)/G(o) subtype. The pharmacological profile of this glutamate receptor negatively coupled to adenylyl cyclase was different from that of the metabotropic Qp glutamate receptor coupled to phospholipase C in striatal neurons and from that of the recently cloned "mGluR2" glutamate receptor, which is negatively coupled to adenylyl cyclase when expressed in non-neuronal cells.
Proc Natl Acad Sci U S A 1992 Sep 01
PMID:Characterization of a metabotropic glutamate receptor: direct negative coupling to adenylyl cyclase and involvement of a pertussis toxin-sensitive G protein. 135 3

The neu/erbB-2 protooncogene encodes a transmembrane tyrosine kinase homologous to receptors for polypeptide growth factors. The oncogenic potential of the presumed receptor is released through multiple genetic mechanisms including a point mutation, truncation of non-catalytic sequences and overexpression. The latter mechanism appears to be relevant to human cancers as elevated expression of the neu/erbB-2 gene is frequently observed in solid tumors of various adenocarcinomas. It is therefore conceivable that strategies aimed at the biochemical mechanism of action of the neu/erbB-2 tyrosine kinase may contribute to the treatment of certain human cancers. To this aim we undertook a multiple research approach consisting of the following directions: (i) The neu/erbB-2 ligand--a systematic screening of potential biological sources of the hypothetical hormone molecule, that presumably binds to the neu/erbB-2 protein, resulted in detection of a candidate activity in the medium of certain cultured transformed cells. Partial purification indicated that the factor is a 30-35 kDa glycoprotein. Further studies revealed several biochemical characteristics of the factor that may be helpful for complete purification and structural analysis of this novel hormone. (ii) Signal transduction by neu/erbB-2--using a chimeric receptor approach and various mutants we found that all the oncogenic forms of the neu/erbB-2 are constitutively coupled, both physically and functionally, to a multi-protein complex of signaling molecules. The latter includes the phosphatidylinositol-specific phospholipase C gamma and a phosphatidylinositol kinase. Thus, the metabolism of inositol lipids is probably a major biochemical pathway utilized by the neu/erbB-2 tyrosine kinase. (iii) Tumor inhibitory antibodies--we generated a panel of monoclonal antibodies to the presumed receptor. Surprisingly, some antibodies almost completely inhibited the growth of tumor cells in athymic mice, whereas one antibody significantly accelerated the rate of tumor growth in animals. Interestingly, the inhibitory antibodies conferred a mature phenotype to cultured breast cancer cells, implicating terminal differentiation in tumor retardation.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Signal transduction by the neu/erbB-2 receptor: a potential target for anti-tumor therapy. 135 18

To identify the genes responsible for blood pressure in the spontaneously hypertensive rat strain, we performed a cosegregation analysis between the genotype and blood pressure in a set of male F2 rats obtained by crossmating SHR with Wistar-Kyoto rats, a parental normotensive strain. Our investigation revealed that the phospholipase C-delta 1 polymorphism, which resulted in missense mutation, cosegregates with the lower blood pressure in SHR, and that PLC-delta 1 gene is located on chromosome 8. On the other hand, we found the lack of cosegregation between blood pressure and the nerve growth factor receptor gene, which is linked to a hypertensinogenic gene locus (denoted as BP/SP-1) on chromosome 10. We propose that PLC-delta 1 gene itself of closely linked gene on chromosome 8 is a new candidate with the hypotensive effect, and that BP-SP1 locus does not directly contribute to blood pressure elevation in original SHR.
Biochem Biophys Res Commun 1992 Sep 30
PMID:Hypotensive effect associated with a phospholipase C-delta 1 gene mutation in the spontaneously hypertensive rat. 135 65

We showed that some of Thy-1 molecules on murine thymocytes are resistant to phosphatidylinositol-specific phospholipase C (PI-PLC) derived from Bacillus thuringiensis. Both immature thymocytes with low CD3 expression and mature thymic T lymphocytes with high CD3 expression carried the PI-PLC-resistant Thy-1, and the PI-PLC-sensitivity of Thy-1 extensively varied among thymocyte subpopulations. In contrast, the same PI-PLC fully hydrolysed the anchor of Thy-1 on peripheral T lymphocytes. When the latter cells were activated with mitogen in vitro, however, some Thy-1 on them became resistant to PI-PLC. We then found that virtually all Thy-1 molecules on thymocytes became sensitive to PI-PLC when they were treated with hydroxylamine that should cleave ester-linked lipids. The result ruled out the possibility that the PI-PLC-resistant Thy-1 had a transmembranous peptide sequence, and suggested the presence of an additional fatty acyl group on the inositol ring of the Thy-1 anchor. In addition, the molecular size of the PI-PLC-resistant membrane-bound Thy-1 was only marginally larger than that of the PI-PLC-sensitive solubilized Thy-1 in detergent-partitioning SDS-PAGE analysis.
Immunobiology 1992 Sep
PMID:T cell maturation stage-linked heterogeneity of the glycosylphosphatidylinositol membrane anchor of Thy-1. 136 Apr 44

Catecholamine (CA) release from adrenal medulla evoked by muscarinic receptor stimulation has been studied using isolated perfused adrenal gland and cultured chromaffin cells from dogs. Muscarine and oxotremorine (1-100 microM), and bethanechol (0.1-1 mM) dose-dependently stimulated CA release. Muscarine-evoked CA release was antagonized with M1-antagonist, pirenzepine and, to a lesser extent, with atropine; and was reduced either by removal of extracellular Ca2+ or treatment with Ca2+ channel blockers. Muscarine caused an increase of 45Ca uptake and 22Na uptake. Tetrodotoxin (TTX) did not affect muscarine-evoked increase of 22Na uptake and CA release. Under the absence of extracellular Ca2+, muscarine stimulated a 45Ca efflux. Muscarine-induced CA release was attenuated by treating the cells with 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate-HCl (TMB-8) which blocks Ca2+ release from the intracellular store. A phospholipase C inhibitor, neomycin, markedly reduced muscarine-induced CA release but not nicotine- and high K(+)-evoked release. Cinnarizine, a Ca2+ channel blocker, attenuated muscarine-evoked but not caffeine-induced CA release and 45Ca efflux in the absence of extracellular Ca2+. Muscarine caused an increase in intracellular free Ca2+ concentration ([Ca2+]i) in the presence of extracellular Ca2+. It caused a similar increase, but to a lesser extent, in the absence of extracellular Ca2+. The increase of [Ca2+]i induced by muscarine without extracellular Ca2+ was reduced by neomycin and cinnarizine. Polymixin B and retinal, which reduced 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced CA release, had little effect on muscarine-induced CA release. Muscarine increased cellular Ins(1,4,5)P3 production, and atropine inhibited this increase.(ABSTRACT TRUNCATED AT 250 WORDS)
Neurochem Int 1992 Sep
PMID:Involvement of Ca2+ entry and inositol trisphosphate-induced internal Ca2+ mobilization in muscarinic receptor-mediated catecholamine release in dog adrenal chromaffin cells. 136 67

Complement plays a role in activating the inflammatory response and has been implicated in the pathogenesis of some inflammatory diseases. With a view toward controlling unwanted C activation, we evaluated the C regulator, human decay accelerating factor (DAF). Three forms of recombinant DAF were purified from transfected Chinese hamster ovary cells: glycophosphatidylinositol (GPI)-linked membrane DAF (mDAF) extracted from cell membranes; spontaneously shed soluble DAF (sDAF) derived from mDAF; and a novel secreted protein (seDAF), generated by deletion of the signal for GPI attachment. We show that all three molecules inhibit both the classical and alternative pathways of C activation. The following observations indicate that mDAF extracted from Chinese hamster ovary cells reincorporates into RBC membranes via its GPI anchor: 1) cells that are preincubated with mDAF and then washed remain fully protected from C-mediated hemolysis; 2) incubation with phosphatidylinositol-specific phospholipase C abolishes this protection; and 3) sDAF and seDAF, which lack a GPI anchor, do not associate with cell membranes. mDAF is a more potent inhibitor of C-mediated hemolysis than either sDAF or seDAF, suggesting that incorporation into cell membranes greatly enhances the efficiency with which DAF inhibits C activation on the cell surface. In contrast, C activation in the fluid phase is inhibited by sDAF and seDAF, but not by mDAF, possibly due to interference by serum lipoproteins. A reversed passive Arthus reaction in guinea pigs was used to evaluate the ability of recombinant seDAF to inhibit C activation in vivo. When administered at dermal sites, seDAF reduced the severity of immune complex-mediated inflammatory reactions induced by a reversed passive Arthus reaction, as judged by both gross and histologic examination. These data indicate that seDAF may be useful as an anti-inflammatory therapeutic.
J Immunol 1992 Sep 01
PMID:Human recombinant soluble decay accelerating factor inhibits complement activation in vitro and in vivo. 138 May 37


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