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)

We have examined the cross talk between adenosine and bradykinin receptors in DDT1 MF-2 smooth muscle cells. Both adenosine and bradykinin mobilized intracellular free calcium via the formation of inositol 1,4,5-trisphosphate in a time- and dose-dependent manner. Adenosine exerted its actions via adenosine A1 receptors as demonstrated by the observations that N6-cyclopentyladenosine, a selective A1 receptor agonist, had an EC50 in the low nanomolar range and that a selective adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine, counteracted adenosine-mediated responses at concentrations typical for signaling via adenosine A1 receptors. Adenosine A1 receptors were coupled to phospholipase C via pertussis toxin-sensitive guanine nucleotide-binding regulatory protein(s) [G protein(s)], whereas bradykinin responses were unaffected by pertussis toxin. When adenosine or N6-cyclopentyladenosine was combined with bradykinin, the resulting formation of inositol 1,4,5-triphosphate was more than additive, and the EC50 value for adenosine and N6-cyclopentyladenosine was shifted to the left by bradykinin, the affinity of which was unaltered. Combining N6-cyclopentyladenosine and bradykinin also synergistically raised intracellular free calcium both at subthreshold levels and at maximal concentrations of the two agonists. The interaction was not dependent upon cAMP. In conclusion, stimulation of adenosine A1 receptors coupled to pertussis toxin-sensitive G protein(s) and bradykinin receptors coupled to pertussis toxin-insensitive G protein(s) synergistically mobilizes intracellular free calcium and inositol 1,4,5-trisphosphate formation.
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PMID:Stimulation of adenosine A1 receptors and bradykinin receptors, which act via different G proteins, synergistically raises inositol 1,4,5-trisphosphate and intracellular free calcium in DDT1 MF-2 smooth muscle cells. 132 31

We have previously demonstrated that human bronchial smooth muscle cells possess a single class of high-affinity binding sites for endothelin 1. In this study, we further characterized the receptor for endothelin 1 and evaluated the signal transduction mechanisms of this peptide. Stimulation of cultured human bronchial smooth muscle cells with endothelin 1 induced mobilization of Ca2+ from both intracellular and extracellular pools with a biphasic increase in cytoplasmic free Ca2+ concentration. Endothelin 1 increased cellular levels of inositol phosphates and diacylglycerol, indicating activation of phospholipase C, but induced production of inositol phosphates in smooth muscle cell membranes only in the presence of guanosine 5'-O-(thiotriphosphate) (GTP gamma S). Treatment of smooth muscle cells with pertussis toxin failed to block the endothelin 1-induced increase in inositol phosphate production and Ca2+ mobilization. These results suggest that the receptor for endothelin 1 in bronchial smooth muscle is coupled to phospholipase C through a pertussis toxin-insensitive G protein. Affinity crosslinking experiments identified the endothelin 1 receptor as a single band with an apparent molecular weight of approximately 70,000 on sodium dodecyl sulfate polyacrylamide gel electrophoresis, further supporting the functional evidence that endothelin 1 receptor belongs to the G protein-linked rhodopsin type of receptor superfamily.
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PMID:Mechanisms of calcium mobilization and phosphoinositide hydrolysis in human bronchial smooth muscle cells by endothelin 1. 165 61

The mechanisms of actions were investigated in cultured rat aortic vascular smooth muscle A-10 cells. The A-10 cells have a single class of high affinity binding sites for ET with an apparent Mr of 65,000-75,000 on SDS-PAGE. Stimulation of cells with ET induces mobilization of Ca2+ from both intra- and extracellular pools to produce a biphasic increase in cytoplasmic free Ca2+ concentration. A dihydropyridine Ca2+ channel antagonist does not inhibit the second plateau phase of the [Ca2+]i increase which is dependent on extracellular Ca2+. ET stimulates phospholipase C to produce inositol trisphosphate and 1,2-diacylglycerol vai a pertussis toxin-insensitive G protein. These results indicate that the receptor activation by ET is coupled to phospholipase C activation and Ca2+ channel gating in vascular smooth muscle cells.
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PMID:The mechanisms of endothelin action in vascular smooth muscle cells. 165 69

The hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C yields the second messengers inositol 1,4,5-trisphosphate (InsP3) and 1,2-diacylglycerol. This activity is regulated by a variety of hormones through G protein pathways. However, the specific G protein or proteins involved has not been identified. The alpha subunit of a newly discovered pertussis toxin-insensitive G protein (Gq) has recently been isolated and is now shown to stimulate the activity of polyphosphoinositide-specific phospholipase C (PI-PLC) from bovine brain. Both the maximal activity and the affinity of PI-PLC for calcium ion were affected. These results identify Gq as a G protein that regulates PI-PLC.
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PMID:Regulation of polyphosphoinositide-specific phospholipase C activity by purified Gq. 184 7

Several classes of growth factors can be distinguished that act through different signal transduction pathways. One class is constituted by the peptide growth factors that bind to receptors with ligand-dependent protein tyrosine kinase activity. Another class of mitogens activates a phosphoinositide-specific phospholipase C via a receptor-linked G protein. An intriguing member of this class is lysophosphatidic acid (LPA). LPA mitogenicity is not dependent on other mitogens and is blocked by pertussis toxin. LPA evokes at least three separate signalling cascades: (i) activation of a pertussis toxin-insensitive G protein mediating phosphoinositide hydrolysis; (ii) release of arachidonic acid in a GTP-dependent manner, but independent of prior phosphoinositide hydrolysis; and (iii) activation of a pertussis toxin-sensitive Gi protein mediating inhibition of adenylate cyclase. The peptide bradykinin mimics LPA in inducing responses (i) and (ii), but fails to activate Gi and to stimulate DNA synthesis. Our results suggest that the mitogenic action of LPA occurs through Gi or a related pertussis toxin substrate and that, unexpectedly, the phosphoinositide hydrolysis pathway is neither required nor sufficient, by itself, for mitogenesis.
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PMID:Growth factor-like action of lysophosphatidic acid: mitogenic signalling mediated by G proteins. 211 27

Ca2+-mobilizing agonists stimulate phospholipase C-mediated phosphatidylinositol 4,5-bisphosphate hydrolysis and inositol trisphosphate (IP3) formation in pulmonary as well as in peripheral vascular endothelial cells (EC). In general, it is believed that receptor-phospholipase C interactions involve a guanine nucleotide regulatory (G) protein. This interaction can be inhibited by Bordetella pertussis toxin in certain cells. Here we report that pertussis toxin catalyzes the [32P]ADP ribosylation of a Mr = 41,000 protein in human umbilical vein EC. However, prior EC treatment with pertussis toxin (250 ng/ml for 20 h) does not inhibit thrombin-induced Ca2+ flux or IP3 formation, despite markedly attenuating the radiolabeling of the Mr = 41,000 protein (less than 5% control). Treatment of digitonin-permeabilized human umbilical vein EC with GTP gamma S, a stable GTP analog, or AIF4-, but not with GDP beta S, stimulates IP3 accumulation. However, GDP beta S inhibits GTP gamma S-induced IP3 accumulation. Although thrombin alone is not very effective in elevating IP3 levels in permeabilized EC, thrombin and GTP gamma S act in a synergistic fashion to increase IP3 accumulation. Overall, these observations are interpreted to indicate that a pertussis toxin-insensitive G protein is a key intermediate in the signaling pathway linking thrombin receptors to phospholipase C in human umbilical vein EC.
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PMID:GTP gamma S increases thrombin-mediated inositol trisphosphate accumulation in permeabilized human endothelial cells. 255 82

Cholecystokinin (CCK) is the major pancreatic secretagogue and acinar cell mitogen. This study was performed to determine by which effector systems CCK regulates tyrosine kinases, phosphatidylinositol (PtdIns) 3-kinase, and phospholipase D (PLD) activities. Pancreatic acini loaded with [3H]myristic acid or [3H]inositol were used to assay PLD and PtdIns 3-kinase. G protein activation with NaF increased particulate and crude cytosolic tyrosine kinase and PLD activities. PLD activation was pertussis toxin sensitive. Inhibition of phospholipase C (PLC) slightly reduced caerulein-stimulated particulate tyrosine kinase and blocked crude cytosolic tyrosine kinase activity without affecting caerulein-induced PLD activity. Ca2+ is an important factor in caerulein stimulation of tyrosine kinase and PLD activities. Protein kinase C and tyrosine kinase inhibition abolished caerulein-activated particulate and crude cytosolic tyrosine kinase and PtdIns 3-kinase activities without any effect on PLD. Wortmannin inhibited PLD and PtdIns 3-kinase activation. Caerulein-induced amylase secretion was partially reduced by tyrosine kinase inhibition, with no effect from wortmannin. Caerulein can stimulate a pertussis toxin-insensitive G protein, leading to particulate tyrosine kinase activation and a Ca(2+)-sensitive cytosolic tyrosine kinase through PLC activation. However, PLD activation by caerulein is pertussis toxin sensitive, cytosolic Ca2+ sensitive, and independent of previous PLC and tyrosine kinase activation.
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PMID:Novel model of integration of signaling pathways in rat pancreatic acinar cells. 757 45

In neutrophils, activation of receptors for the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) leads to changes in intracellular events such as phosphoinositide turnover and Ca2+ mobilization. Studies have shown that activation of the cloned fMLP receptor can also lead to inhibition of cyclic AMP (cAMP) accumulation [Lang, Boulay, Li and Wollheim (1993) EMBO J. 12, 2671-2679; Uhing, Gettys, Tomhave, Snyderman and Didsbury (1992) Biochem. Biophys. Res. Commun. 183, 1033-1039]. These responses are apparently mediated through pertussis toxin-sensitive Gi proteins. Since other chemotactic factor receptors can couple to multiple G proteins, we examined the ability of the fMLP receptor to utilize a pertussis toxin-insensitive G protein, Gz, in its signal transduction pathways. The human fMLP receptor was transiently expressed in 293 and Ltk- cells, and subsequently assayed for receptor-mediated inhibition of cAMP accumulation and stimulation of phosphoinositide-specific phospholipase C. In transfected 293 cells, fMLP inhibited choriogonadotropin-stimulated cAMP accumulation by 50% and the response could be abolished by pertussis toxin. Co-expression of the fMLP receptor with the alpha subunit of Gz rendered the fMLP response pertussis toxin-insensitive, indicating that the endogenous Gi proteins can be substituted efficiently by Gz. In contrast, Ltk- cells expressing the fMLP receptor were able to respond to fMLP with an increase in the production of inositol phosphates, but this response was completely abolished by pertussis toxin even in cells co-expressing the alpha subunit of Gz. Thus, although both signalling pathways appeared to utilize Gi-like proteins, Gz can only replace Gi in mediating inhibition of cAMP accumulation, and not in the stimulation of phospholipase C. Differential interaction with Gz might represent a novel mechanism by which fMLP receptors regulate intracellular events.
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PMID:Differential coupling of the formyl peptide receptor to adenylate cyclase and phospholipase C by the pertussis toxin-insensitive Gz protein. 761 76

We evaluated the G protein selectivity of chimeric M1 and M2 muscarinic cholinergic receptors in which either the third intracellular (I3) loop or the N-terminal portion of this loop (the I3N peptide) was replaced by the corresponding sequence from the beta 1-adrenergic receptor. The chimeras retained agonist-dependent G protein regulatory activity, but were completely promiscuous among potential G protein targets. When expressed in transfected cells, the chimeric receptors activated adenylyl cyclase, the major target of the beta-adrenergic receptor, and activated phospholipase C via a pertussis toxin-insensitive G protein, presumably a Gq. Gs is not a target of either muscarinic receptor, and Gq is not a cellular target of either the M2 muscarinic or beta-adrenergic receptor. When co-reconstituted into phospholipid vesicles with purified G proteins, the chimeric receptors were completely nonselective among all G proteins tested. They activated Gi, G(o), Gz, and Gs with similar efficiencies. This promiscuity was largely suppressed, both in transfected cells and in reconstituted vesicles, by the additional replacement of the second intracellular (I2) loop of the beta-adrenergic receptor. Such double substitutions created receptors specific for Gs, the target of the beta-adrenergic receptor. These findings suggest that G protein specificity depends on the proper combination of multiple regions on a receptor's cytoplasmic surface. In addition, the promiscuous receptors described here may be useful for regulating novel G proteins whose natural regulators are not yet known.
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PMID:Chimeric muscarinic cholinergic:beta-adrenergic receptors that are functionally promiscuous among G proteins. 803 54

alpha 1-Adrenergic receptors (ARs) are members of the G protein-coupled receptor superfamily. alpha 1-AR subtypes mediate the effects of the sympathetic nervous system, especially those involved in cardiac homeostasis. To investigate signal transduction by a novel subtype (alpha 1D), which we recently cloned, and to compare it with that by the previously characterized alpha 1B-AR, we assessed the ability of each subtype to activate polyphosphoinositide (PI) metabolism, cAMP accumulation, and arachidonic acid release in Chinese hamster ovary (CHO) and COS-1 cells expressing these subtypes after stable or transient transfection, respectively. In COS-1 and CHO cells, both the alpha 1D- and alpha 1B-AR were found to couple to PI hydrolysis through a pertussis toxin-insensitive G protein. Both alpha 1-AR subtypes also increased intracellular cAMP by an indirect mechanism, although this effect was observed only in COS-1 cells and not in CHO cells. Interestingly, alpha 1-AR-stimulated arachidonic acid release was also demonstrated for both subtypes in COS-1 cells. This release was mediated through phospholipase A2 activation and involved a pertussis toxin-sensitive G protein. alpha 1-AR-stimulated arachidonic acid release was dependent upon extracellular calcium and was inhibited by 1 microM nifedipine. Inhibitors of protein kinase C, phospholipase C, and diacylglycerol lipase did not alter alpha 1-AR-stimulated release of arachidonic acid. These findings indicate that in COS-1 cells alpha 1-AR-stimulated arachidonic acid release is most likely coupled to dihydropyridine-sensitive L-type calcium channels via a pertussis toxin-sensitive G protein. The influx of extracellular calcium then stimulates phospholipase A2 to release arachidonic acid. alpha 1-AR-stimulated arachidonic acid release could also be demonstrated in CHO cells and was pertussis toxin sensitive but nifedipine insensitive. These cells were also unresponsive to Bay K8644, indicating a lack of voltage-sensitive calcium channels in CHO cells. Nevertheless, alpha 1-AR activation increased intracellular Ca2+ levels, as assessed by fura-2 fluorescence studies. Neomycin blocked both alpha 1-AR-stimulated PI hydrolysis and increases in intracellular Ca2+ levels but did not inhibit the increase in arachidonic acid release. Taken together, these data indicate that in CHO cells alpha 1-ARs can couple directly to phospholipase A2 activation via a pertussis toxin-sensitive pathway. Thus, in these model systems we demonstrate for the first time that a single alpha 1-AR subtype can activate multiple distinct signal transduction pathways, in which receptor-effector coupling is modulated by distinct G proteins.
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PMID:Coupling of expressed alpha 1B- and alpha 1D-adrenergic receptor to multiple signaling pathways is both G protein and cell type specific. 823 29


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