Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preincubation with an alpha 2-adrenergic agonist sensitized subsequent forskolin- and vasoactive intestinal peptide-stimulated cyclic AMP production in HT29 cells, a human colonic adenocarcinoma cell line. Preincubation with somatostatin, another agonist negatively coupled to adenylate cyclase, sensitized forskolin-stimulated cyclic AMP production to a lesser extent. alpha 2-Adrenergic agonist preincubation also resulted in desensitization as indicated by a shift to the right in the dose-response curve of a subsequent challenge by an alpha 2-adrenergic agonist. In an effort to elucidate the mechanism for sensitization, we examined protein kinase C and the Na+/H+ antiporter. Whereas these components had marked effects on forskolin stimulation, there was no effect on sensitization. Changes in the concentration of extra-cellular Ca2+ or Mg2+ had no effect on either forskolin stimulation or sensitization. Pertussis toxin pretreatment caused a time-dependent decrease in sensitization, an attenuation of inhibition of cyclic AMP production, and a decrease in subsequent [32P]ADP-ribosylation by pertussis toxin. The time course for these three events was similar, implicating the inhibitory guanine nucleotide regulatory protein in the mechanism for alpha 2-adrenergic receptor-mediated sensitization of forskolin-stimulated cyclic AMP production. In addition, pertussis toxin dramatically decreased forskolin-stimulated cyclic AMP production, although with a different time course. These results suggest that the mechanism of sensitization is via an as yet undefined sequence of biochemical events that includes the inhibitory guanine nucleotide regulatory protein, but does not include inhibition of adenylate cyclase nor activation of the Na+/H+ antiporter.
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PMID:Characterization and possible mechanisms of alpha 2-adrenergic receptor-mediated sensitization of forskolin-stimulated cyclic AMP production in HT29 cells. 284 62

Preincubation of human neutrophils with recombinant tumor necrosis factor alpha has previously been shown by us to enhance superoxide production of neutrophils in response to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine, and the phorbol ester, phorbol myristate acetate. In this study, we further investigate the biochemical basis for this enhancement. We found that in neutrophils, TNF by itself does not induce: (1) an influx of sodium, (2) an alteration in activity or translocation of the calcium and phospholipid dependent protein kinase (C-kinase), or (3) a release of arachidonic acid from preloaded cells. TNF did, however, induce a time- and concentration-dependent increase in the phosphorylation of several neutrophil proteins, with the most dramatic concentration dependent increase in a 64,000 Da protein. Finally, the enhancement of O2 production by pretreatment of neutrophils with TNF was found to be independent of a pertussis toxin-sensitive guanine nucleotide regulatory protein.
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PMID:Biochemical mechanisms involved in the priming of neutrophils by tumor necrosis factor. 284 26

The effect of the new cardiotonic agent sulmazole on the guanine nucleotide regulatory protein-adenylate cyclase system was studied in rat adipocyte membranes. The inotrope enhanced basal adenylate cyclase activity by 46%. This stimulation occurred only at GTP concentrations (5 microM) sufficient to activate Gi. This stimulatory effect of sulmazole was abolished after functional inactivation of Gi, either by pertussis toxin or by using 10 nM GTP in the assay mixture, suggesting an important role of an active Gi in this process. Similarly, sulmazole enhanced isoproterenol-, forskolin-, and fluoride-stimulated adenylate cyclase activity by 33, 34, and 45%, respectively. However, when these latter experiments were performed after inactivation of Gi, sulmazole actually inhibited by approximately 25% adenylate cyclase activity stimulated by 1 and 10 microM isoproterenol. Under similar treatment conditions, enhancement of forskolin- and fluoride-stimulated activity by sulmazole was abolished. Sulmazole inhibited in a dose-dependent manner pertussis toxin- and cholera toxin-catalyzed labeling of Gi and Gs, respectively, with the respective inhibition observed at 100 microM of the inotrope being 29% and 56% of control. In addition, sulmazole inhibited PGE1 and isoproterenol-stimulated [3H]GDP release from Gi and Gs to 32% and 64% of control, respectively. Finally, the inotrope completely abolished PGE1-stimulated [3H]Gpp(NH)p binding with IC50 in the low micromolar range. These findings suggest that, whereas sulmazole inhibits the functioning of Gi and (to a lesser extent) Gs at low micromolar concentrations, expression of these effects on adenylate cyclase activity requires high micromolar to low millimolar concentrations of the drug. Thus, it appears sulmazole inhibits the function of Gi by decreasing its activation process, i.e., GTP-GDP exchange. Effects on Gs are manifested (at least in terms of adenylate cyclase activity) only after inactivation of Gi.
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PMID:The new positive inotrope sulmazole inhibits the function of guanine nucleotide regulatory proteins by affecting GTP turnover. 284 44

1. In the intact guinea-pig myometrium, carbachol and oxytocin stimulated a specific receptor-mediated phospholipase C activation, catalysing the breakdown of PtdIns(4,5)P2 with the sequential generation of InsP3, InsP2 and InsP. Stimulation of muscarinic receptors also triggered an inhibition of cyclic AMP accumulation caused by prostacyclin. 2. NaF plus AlCl3 mimicked the effects of carbachol and oxytocin by inducing, in a dose-dependent manner, the generation of all three inositol phosphates as well as uterine contractions. AlCl3 enhanced the fluoride effect, supporting the concept that A1F4- was the active species. Under similar conditions, fluoroaluminates activated the guanine nucleotide regulatory protein Gi, reproducing the inhibitory effect of carbachol on cyclic AMP concentrations. 3. Both carbachol- and oxytocin-mediated increases in inositol phosphates, as well as contractions, were insensitive to pertussis toxin, under conditions where the expression of Gi was totally prevented. Cholera toxin, which activates Gs and enhances cyclic AMP accumulation, failed to affect basal or oxytocin-evoked inositol phosphate generation, but induced a slight, though consistent, attenuation of the muscarinic inositol phosphate response, which was similarly evoked by forskolin. 4. The data provide evidence that, in the myometrium, (a) a G protein mediates the generation of inositol phosphates and the Ca2+-dependent contractile event, (b) the relevant G protein that most probably couples muscarinic and oxytocin receptors to phospholipase C is different from Gi and Gs, the proteins that couple receptors to adenylate cyclase, and (c) cyclic AMP does not seem to control the phosphoinositide cycle, but rather exerts a negative regulation at the muscarinic-receptor level.
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PMID:Fluoroaluminates mimic muscarinic- and oxytocin-receptor-mediated generation of inositol phosphates and contraction in the intact guinea-pig myometrium. Role for a pertussis/cholera-toxin-insensitive G protein. 284 25

Thrombin exhibited diverse effects on mouse 3T3 fibroblasts. It (a) decreased cAMP in the cell suspension, (b) inhibited adenylate cyclase in the Lubrol-permeabilized cell suspension in a GTP-dependent manner, increased releases of (c) arachidonic acid and (d) inositol from the cell monolayer prelabeled with these labeled compounds, (e) increased 45Ca2+ uptake into the cell monolayer, and (f) increased 86Rb+ uptake into the cell monolayer in a ouabain-sensitive manner. Most of the effects were reproduced by bradykinin, platelet-activating factor, and angiotensin II. The receptors for these agonists are thus likely to be linked to three separate effector systems: the adenylate cyclase inhibition, the phosphoinositide breakdown leading to Ca2+ mobilization and phospholipase A2 activation, and the Na,K-ATPase activation. Among the effects of these agonists, (a), (b), (c), and (e) were abolished, but (d) and (f) were not, by prior treatment of the cells with islet-activating protein (IAP), pertussis toxin, which ADP-ribosylates the Mr = 41,000 protein, the alpha-subunit of the inhibitory guanine nucleotide regulatory protein (Ni), thereby abolishing receptor-mediated inhibition of adenylate cyclase. The effects (a), (c), (d), and (e) of thrombin, but not (b), were mimicked by A23187, a calcium ionophore. The effects of A23187, in contrast to those of receptor agonists, were not affected by the treatment of cells with IAP. Thus, the IAP substrate, the alpha-subunit of Ni, or the protein alike, may play an additional role in signal transduction arising from the Ca2+-mobilizing receptors, probably mediating process(es) distal to phosphoinositide breakdown and proximal to Ca2+ gating.
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PMID:Receptor-mediated inhibition of adenylate cyclase and stimulation of arachidonic acid release in 3T3 fibroblasts. Selective susceptibility to islet-activating protein, pertussis toxin. 286 Jan 11

Prostaglandin E2 (PGE2) was found to bind specifically, reversibly, and in a protein-dependent manner to a single class of high affinity (KD approximately equal to 20 nM) binding sites in membranes prepared from canine renal outer medulla. PGE2 binding activity was solubilized from these membranes in a stable form (t1/2 greater than 14 days) in the absence of ligand in 75% yields using digitonin. The characteristics of PGE2 binding to membranes and solubilized protein were similar with respect to pH dependence, KD for PGE2, and order of potency of prostaglandins (PGE2 approximately PGE1 greater than PGF2 alpha greater than PGD2) in inhibiting the binding of [3H]PGE2. Importantly, the extents of binding of PGE2 to membranes and to a solubilized preparation partially purified by chromatography on wheat germ agglutinin-Affi-Gel 10 were both increased about 2-fold by GDP and GTP and its analogs. Treatment of the digitonin-solubilized PGE2 binding activity with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS) rendered the binding activity insensitive to stimulation by GTP and decreased the apparent molecular weight of the peak of PGE2 binding activity from about 175,000 to about 65,000. These results suggest that the PGE2 binding activity resides in a protein which is tightly associated with, but distinct from, a guanine nucleotide regulatory (N) protein. PGE2 (greater than or equal to 10 nM) was found to stimulate GTPase activity of renal outer medullary membranes, and this stimulation was eliminated by pretreatment of membranes with pertussis toxin and NAD, but not cholera toxin and NAD. Treatment of both particulate and solubilized preparations of PGE2 binding activity with pertussis toxin plus NAD also eliminated the ability of GTP to stimulate PGE2 binding. This evidence indicates that it is the inhibitory guanine nucleotide regulatory protein, Ni, with which the PGE2 binding activity is associated. Thus, this PGE2 binding activity is an inhibitory PGE2 receptor, quite possibly one that mediates inhibition of vasopressin-induced cAMP formation in the medullary thick ascending limb and/or collecting tubule of the kidney.
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PMID:Association of a solubilized prostaglandin E2 receptor from renal medulla with a pertussis toxin-reactive guanine nucleotide regulatory protein. 287 97

Cyclic AMP accumulation in rat parotid slices is only transiently stimulated by isoproterenol (Harper, J.F. and Brooker, G. Molec. Pharmacol. 13:1048-1059, 1977); the progressive loss of isoproterenol effect is termed desensitization. In this report we show that desensitized cyclic AMP accumulation is associated with desensitization of adenylate cyclase in subsequently prepared membranes and in adenylate cyclase that has been detergent-solubilized from desensitized membranes. Adenylate cyclase in membranes made from isoproterenol-desensitized tissue is desensitized to both the stimulating effects of isoproterenol with 6 mM MgCl2 and of forskolin with 30 mM MnCl2. We have previously determined (Harper, J.F. J. Cyclic Nucleo. Prot. Phosphoryl. Res. 9:401-414, 1984) that cyclic AMP accumulation desensitized to isoproterenol is rapidly counteracted by 1 microM forskolin but not 0.1 microM forskolin. Similarly, if 1 microM forskolin was included in the desensitizing incubation with isoproterenol then adenylate cyclase subsequently prepared was not desensitized. Development of desensitized adenylate cyclase was only partially affected by 0.1 microM forskolin. Desensitization is counteracted by forskolin only on intact cells. Once tissue is homogenized, desensitized adenylate cyclase does not respond as well to forskolin as does control adenylate cyclase. The site of desensitization appears to be at or near the adenylate cyclase catalytic unit. Desensitization of adenylate cyclase catalytic activity remains demonstrable after membranes are solubilized with CHAPS. The adenylate cyclase activity remaining in the supernatant following solubilization of desensitized membranes is depressed to nearly the same extent as found in the membranes. Further, desensitized adenylate cyclase in membrane preparations and after solubilization is desensitized to stimulatory effects of forskolin with 30 mM MnCl2, a condition under which forskolin is probably acting directly on the adenylate cyclase catalytic unit. Desensitization appears not to be dependent on activity of the inhibitory guanine nucleotide regulatory protein (Gi), since pertussis toxin is without effect on desensitization of cyclic AMP accumulation to isoproterenol.
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PMID:Desensitization in rat parotid to beta-adrenergic agonists and counteracting effects of forskolin are conserved in membrane and detergent-solubilized adenylate cyclase catalyst activity. 287 14

The rate of glucose utilization in isolated pancreatic islets of the rat was inhibited by the alpha 2-adrenoceptor agonists clonidine and epinephrine. Yohimbine reversed the inhibition. alpha 1 or beta-adrenoceptor agonists had little or no effect on glucose utilization. Stimulation of muscarinic receptors by carbamylcholine reversed the effect of clonidine. Pertussis toxin blocked the effect of clonidine on glucose utilization, and potentiated the response to carbamylcholine. 8-Bromo-cAMP did not affect glucose utilization in the presence of clonidine. Thus, alpha 2-adrenoceptors negatively modulate glucose utilization, and the effect is mediated by an inhibitory guanine nucleotide regulatory protein, but not by cAMP.
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PMID:Alpha 2-adrenergic inhibition of pancreatic islet glucose utilization is mediated by an inhibitory guanine nucleotide regulatory protein. 288 23

The addition of bradykinin to NG108-15 cells resulted in an increase in the intracellular Ca2+ concentration [( Ca2+]i) and the formation of inositol monophosphate, inositol bisphosphate, and inositol trisphosphate in these cells. The bradykinin-stimulated formation of inositol polyphosphates in plasma membrane preparations was dependent on the presence of GTP or guanosine-5'-O-thiotriphosphate (GTP gamma S) but not of GDP. GTP gamma S, unlike GTP, increased the basal formation of inositol polyphosphate in NG108-15 membranes. Iontophoretic injection of GTP gamma S into single cells induced increases in [Ca2+]i. These effects of bradykinin and GTP gamma S on [Ca2+]i and the formation of inositol phosphates in the intact cells and membranes were not affected by treatment of the cells with pertussis toxin or cholera toxin. Data on binding of bradykinin to membrane preparations indicated the presence of two classes of binding sites with Kd values of 0.80 +/- 0.26 and 9.63 +/- 0.13 nM. Approximately 74% of the receptors were in the high affinity state. In the presence of guanyl-5'-yl-imidodiphosphate [Gpp(NH)p], the high affinity sites in the membrane preparations were converted to low affinity sites with no change in the total receptor number. These toxin treatments had no effect on binding of bradykinin to its receptors. Thus, these results indicate that a guanine nucleotide regulatory protein, which is not a substrate of pertussis toxin or cholera toxin, is involved in mediating the effects of bradykinin on membrane-bound phosphoinositide-specific phospholipase C to induce the increase of cytosolic calcium.
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PMID:Role of a protein regulating guanine nucleotide binding in phosphoinositide breakdown and calcium mobilization by bradykinin in neuroblastoma X glioma hybrid NG108-15 cells: effects of pertussis toxin and cholera toxin on receptor-mediated signal transduction. 288 51

The formation of the second messenger cyclic AMP (cAMP) is known to be coupled to its receptor via a guanine nucleotide regulatory protein, GS. Ca2+-mobilizing receptors stimulate the hydrolysis of phosphatidylinositol bisphosphate (PtdIns(4,5)P2), which generates two intracellular signals Ins(1,4,5)P3 and diacylglycerol. We review the evidence that this signalling system is also composed of three types of proteins: receptor, G-protein and effector. The G-protein that couples to the effector, polyphosphoinositide phosphodiesterase (PPI-PDE), is a novel G-protein, GP, which is a substrate for pertussis toxin in some cells (e.g. neutrophils and platelets) but not others (e.g. pancreatic acinar cells and GH3 cells). This implies that GP is not a single G-protein but encompasses a family of proteins that can activate PPI-PDE. We have also identified a role for another G-protein, GE, which is involved in the secretory process in mast cells and neutrophils. In this case, neither the receptor nor effector has been identified and the main evidence for proposing this second G-protein is based on the ability of guanine nucleotide analogues (e.g. GTP gamma S) to stimulate secretion independently of PPI-PDE activation.
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PMID:G-proteins, the inositol lipid signalling pathway, and secretion. 290 37


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