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)

The signal transduction of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2), cyclooxygenase products of arachidonic acid, was investigated in smooth muscle preparations and 1321N1 human astrocytoma cells. While PGE2 has been known to stimulate (via EP2 receptor) or inhibit (via EP3 receptor) adenylate cyclase, PGE2 activated phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phospholipase C (PLase C) in non-vascular smooth muscles (via EP1 receptor), resulting in accumulations of inositol trisphosphate (IP3) and diacylglycerol to elicit intracellular Ca2+ mobilization. On the other hand, STA2, a TXA2 receptor analogue, also accumulated IP3 in human astrocytoma cells. [3H]SQ 29548, a TXA2 receptor antagonist, specifically bound to astrocytoma membranes. TXA2-receptor antagonists (ONO NT-126, S-145, SQ29548 and ONO3708) concentration-dependently inhibited PIP2-specific PLase C activation by STA2, and they also inhibited [3H]SQ 29548 binding in human astrocytoma cells. The Ki value of each antagonist in PIP2-specific PLase C inhibition was similar to that in [3H]SQ29548 binding inhibition. In membrane preparations, STA2 activated PIP2-specific PLase C in the presence of GTP gamma S. Pertussis toxin (IAP) did not affect STA2-induced PLase C activation. The results suggest that stimulation of TXA2 receptors activates PIP2-specific PLase C via an IAP-insensitive G-protein.
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PMID:[Signal transduction of prostaglandin E2 and thromboxane A2]. 131 76

Goldfish brain has a high density of [3H]kainate-binding sites, a subpopulation of which appears to be coupled to a pertussis toxin-sensitive G protein. We show here that a purified kainate receptor preparation reconstituted into phospholipid vesicles exhibits guanine nucleotide-sensitive high-affinity [3H]kainate binding. Pertussis toxin treatment abolishes the guanine nucleotide-sensitive portion of the [3H]kainate binding, and kainate promotes [3H]guanosine 5'-[beta,gamma-imido]triphosphate binding and [gamma-32P]GTP hydrolysis. Guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]) decreases the apparent Stokes radius of the soluble purified receptor preparation, consistent with dissociation of the kainate receptor-G protein complexes. The affinity-purified preparations contain proteins of 45, 41, and 35 kDa. The 45- and 41-kDa proteins crossreact with antibodies against the kainate receptor cloned from frog brain. The 35-kDa protein is recognized by an antiserum (SW) directed against the beta subunit of G proteins. When kainate receptors are purified in the presence of GTP[gamma S], the 35-kDa protein is no longer present. Also, [3H]kainate affinity is decreased and is no longer guanine nucleotide sensitive. Upon reconstitution with purified G proteins, high-affinity guanine nucleotide-sensitive binding and kainate-stimulated GTPase activity can be restored. These observations indicate that a kainate receptor from goldfish brain functionally interacts with a pertussis toxin-sensitive G protein.
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PMID:Coupling of a purified goldfish brain kainate receptor with a pertussis toxin-sensitive G protein. 131 52

Adenylyl cyclase in rat adipose cells is stimulated by ligands for Rs receptors (e.g. isoproterenol) and inhibited by ligands for Ri receptors (e.g. adenosine). In contrast, Rs receptors mediate inhibition and Ri receptors mediate augmentation of insulin-stimulated glucose transport activity by a process independent of changes in cellular cAMP-dependent protein kinase activity [Kuroda M., Honnor R. C., Cushman S. W., Londos C. and Simpson I. A. (1987) J. biol. Chem. 262, 245-253]. The present study examines the possible role of G-proteins in the regulation of insulin-stimulated glucose transport activity by Rs and Ri receptors. First, conditions were established that permit intoxication of isolated rat adipocytes by cholera and pertussis toxins without compromising cell integrity. Effectiveness of toxin treatment was monitored by examining adenylyl cyclase activity in isolated plasma membranes. Secondly, neither toxin interfered with the ability of a maximal concentration insulin to initiate the glucose transport response. Thirdly, pertussis toxin eliminated the augmenting effects of adenosine on insulin-stimulated glucose transport activity, but enhanced the inhibitory effects of isoproterenol. Findings with ligands for other Ri receptors (nicotinic acid and prostaglandin E2) mirrored those with adenosine. Finally, cholera toxin elicited a modest depression of transport activity, and only in the absence of an Ri ligand (e.g. adenosine). Furthermore, in contrast to the enhanced stimulation of adenylyl cyclase by isoproterenol and GTP, cholera toxin eliminated the inhibitory effect of isoproterenol on transport activity. The augmentative effects of adenosine on transport activity were unchanged. Measurements of (-/+cAMP) cAMP-dependent protein kinase activity ratios reinforce the notion that modulation of glucose transport activity is independent of changes in cAMP. We conclude that regulation of glucose transport activity by Rs and Ri receptors is mediated by the G-proteins, Gs and Gi (or other toxin substrates), respectively. Inasmuch as such regulation occurs at the plasma membrane and appears to be cAMP-independent, it is suggested that glucose transporters may be direct targets for receptor: G-protein interactions.
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PMID:Cholera and pertussis toxins modify regulation of glucose transport activity in rat adipose cells: evidence for mediation of a cAMP-independent process by G-proteins. 131 47

In previous studies we have identified and isolated a prostaglandin E2 (PGE2) receptor from cardiac sarcolemmal (SL) membranes. Binding of PGE2 to this receptor in permeabilized SL vesicles inhibits adenylyl cyclase activity. The purpose of this study was to determine if the cardiac PGE2 receptor is coupled to adenylyl cyclase via a pertussis toxin sensitive guanine nucleotide binding inhibitory (Gi) protein. Incubation of permeabilized SL vesicles in the presence of 100 microM 5'-guanylamidiophosphate, Gpp(NH)p, a nonhydrolyzable analogue of GTP, resulted in a shift in [3H]PGE2 binding from two sites, one of high affinity (KD = 0.018 +/- 0.003 nM) comprising 7.7% of the total available binding sites and one of lower affinity (KD = 1.9 +/- 0.7 nM) to one site of intermediate affinity (KD = 0.52 +/- 0.01 nM) without a significant change in the total number of PGE2 binding sites. A shift from two binding sites to one binding site in the presence of Gpp(NH)p was also observed for [3H]dihydroalprenolol binding to permeabilized cardiac SL. When permeabilized SL vesicles were pretreated with activated pertussis toxin, ADP-ribosylation of a 40- to 41-kDa protein corresponding to Gi was observed. ADP-ribosylation of SL resulted in a shift in [3H]PGE2 binding to one site of intermediate affinity without significantly changing the number of binding sites. In alamethicin permeabilized SL vesicles, 1 nM PGE2 significantly decreased (30%) adenylyl cyclase activity. Pretreatment with activated pertussis toxin overcame the inhibitory effects of PGE2. These results demonstrate that the cardiac PGE2 receptor is coupled to adenylyl cyclase via a pertussis toxin sensitive Gi protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin E2 receptors in the heart are coupled to inhibition of adenylyl cyclase via a pertussis toxin sensitive G protein. 131 18

Atopic dermatitis (AD) is characterized by a variety of abnormal physiologic and pharmacologic responses in the skin. Leukocyte abnormalities of the cyclic nucleotide system include increased cAMP phosphodiesterase (PDE) and adenylyl cyclase activities. We have evaluated the possibility that a defect of the inhibitory GTP-binding protein (Gi) might cause inadequate modulation of adenylyl cyclase activity in AD leukocytes. We carried out a series of studies assessing adenylyl cyclase and Gi subunits in monocyte membranes. Using both pertussis toxin ribosylation and direct monoclonal antibody labeling of Gi proteins, we have shown evidence for a decrease or possible absence of one of the Gi proteins in atopic monocyte membranes. A genetic defect or toxin-mediated abnormality in leukocyte membrane Gi could account for these findings. Increased cAMP degradation by PDE may be a compensatory mechanism for increased cAMP synthesis that is regulated by GTP-binding proteins. But this increased PDE activity also rendered AD leukocytes hypo-responsive to immunofunction regulatory signals mediated by cAMP.
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PMID:Relationship between increased cyclic AMP-phosphodiesterase activity and abnormal adenylyl cyclase regulation in leukocytes from patients with atopic dermatitis. 131 24

Studies were performed to examine the regulation of atrial natriuretic peptide- (ANP) stimulated guanylate cyclase in the the inner medulla. Primary cultures of rat inner medullary collecting tubular cells exposed to 10(-7) M ANP increased cGMP formation to 31.2 +/- 1.8 compared to the basal production of 2.1 +/- 0.6 fm/micrograms protein. This response did not appear to be transduced via a Gi protein, as preincubation with pertussis toxin did not alter the response to 10(-7) M ANP, and saponized cells exposed to 10 microM GTP gamma S did not enhance the response to ANP (77.3 +/- 5.9 vs. 86.7 +/- 6.3 g/micrograms). Likewise, changes in extracellular Ca2+ from 0.5 to 3.0 mM, decrements in intracellular Ca2+ with EGTA or increments in intracellular Ca2+ with ionomycin (5 microM) did not significantly alter the response to ANP. Neither activation of protein kinase A with forskolin (36.5 +/- 5.1) nor of protein kinase C with s,n-1,2-dioctanoylglycerol (33.2 +/- 2.5) altered the response to 10(-7) M ANP (32.2 +/- 3.3, NS). As the inner medullary environment was hypertonic, the effect of altering tonicity was studied. Cells grown for 48 hours in hypertonic media (600 mOsm/kg H2O) displayed enhanced response to 10(-8) and 10(-7) M ANP when osmolality was raised by either Na+ alone or in combination with urea, but not by urea alone. Our studies demonstrate that ANP-stimulated guanylate cyclase is insensitive to alterations in either intra- or extracellular Ca2+, is not subject to inhibition by protein kinase, and does not involve a pertussis-sensitive G protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of atrial natriuretic peptide-stimulated cGMP production in the inner medulla. 131 78

The mechanisms of action of lithium and antidepressants were investigated with reference to effects of these drugs on monoaminergic receptors and receptor-coupled adenylate cyclase systems in rat brain. Oral administration of lithium carbonate for 21 days decreased significantly the density of beta-adrenergic receptors in rat cerebral cortex, which is the same change as reported as the result of long-term treatment with many antidepressants. With regard to 5-hydroxytryptamine (5-HT) receptor subtypes, lithium treatment reduced the maximum number of 5-HT1A receptors in rat hippocampus but not in cerebral cortex, whereas repetitive injections with imipramine or desipramine did not. beta-Adrenoceptor-coupled adenylate cyclase activity was subsensitized by long-term lithium treatment in consistency with above-mentioned down-regulation of beta-adrenergic receptors. Stimulation of adenylate cyclase activity by non-hydrolyzable GTP analogue, guanyl-5'-ylimidodiphosphate (Gpp(NH)p), was, however, unaltered in lithium-treated rats as compared with controls. On the other hand, 5-HT1A-mediated inhibition of forskolin-stimulated adenylate cyclase in rat hippocampal membranes was not altered by chronic treatment with lithium or antidepressants. Gpp(NH)p-induced inhibition of forskolin-stimulated adenylate cyclase activity was not influenced by lithium treatment, either. [3H]Forskolin binding to rat cerebral cortex, which is assumed to be associated with the activated complex of catalytic subunit of adenylate cyclase and stimulatory guanine nucleotide-binding regulatory proteins (Gs), was not changed by administration of lithium or antidepressants under any condition studied. Pertussis toxin (islet-activating protein, IAP) sensitive G proteins (Gi/Go) as determined by using IAP-catalyzed [32P]ADP-ribosylation was not altered by lithium- or antidepressant-treatment, either. The implication of these results is discussed with a view of clarifying the mechanisms of action of these thymoleptic drugs.
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PMID:[Effects of lithium and antidepressants on monoaminergic receptors and receptor-coupled adenylate cyclase system in rat brain]. 131 19

The effects of guanosine 5'-[beta-thio]triphosphate (GTP beta[S]) on G proteins have been examined in Chinese hamster lung fibroblasts (CCL39 line) permeabilized with alpha-toxin from Staphylococcus aureus. Although much less effective than guanosine 5'-[gamma-thio]triphosphate (GTP gamma[S]), both (Rp) and (Sp) diastereomers of GTP beta[S] were found to activate three G protein-mediated pathways: inhibition of forskolin-stimulated adenylate cyclase (mediated by Gi), potentiation of receptor-mediated activation of adenylate cyclase (mediated by Gs), and activation of phosphoinositide breakdown (mediated by Gp). Activation of Gi and Gs occurred above 3 microM-GTP beta[S], but activation of Gp only occurred above 100 microM-GTP beta[S]. Moreover, the order of effectiveness of the two diastereomers was not the same for the three G protein-mediated processes. Whereas both Gi and Gs were more effectively activated (about 5-fold) by (Sp)-GTP beta[S] than by (Rp)-GTP beta[S], Gp showed a marked preference for the (Rp) isomer. Indeed, (Rp)-GTP beta[S] induced the formation of inositol phosphates with a shorter latency and was a better competitor of GDP for binding to Gp than the (Sp) isomer. These results point to different guanine nucleotide-binding properties for Gi and Gs on the one hand and Gp on the other. At least two distinct Gp proteins, differing by their sensitivity to pertussis toxin, are present in CCL39 cells. Since pretreatment of cells with pertussis toxin completely suppressed the effects of (Rp)-GTP beta[S] on Gi, while only slightly attenuating its effects on Gp, we believe that it is the pertussis toxin-insensitive Gp which prefers the (Rp) isomer. Therefore (Rp)-GTP beta[S] may be a valuable tool for the selective activation and the biochemical characterization of this pertussis toxin-insensitive Gp.
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PMID:Activation of G proteins by (Rp) and (Sp) diastereomers of guanosine 5'-[beta-thio]triphosphate in hamster fibroblasts. Differential stereospecificity of Gi, Gs and Gp. 131 29

The AP4 (2-amino-4-phosphonobutyrate) receptor is a presynaptic glutamate receptor that inhibits transmitter release via an unknown mechanism. We examined the action of L-AP4 on voltage-dependent calcium currents and excitatory synaptic transmission on cultured olfactory bulb neurons using whole-cell voltage-clamp methods. In neurons dialyzed with GTP, L-AP4 inhibited high-threshold calcium currents evoked in barium solutions. The inhibition was irreversible in the presence of GTP-gamma-S and blocked by removing intracellular Mg2+ or by preincubation with pertussis toxin (PTX), consistent with the involvement of a PTX-sensitive G-protein. Dialysis with staurosporine or buffering of intracellular calcium to pCa less than 8 did not block the action of L-AP4, suggesting that protein phosphorylation or release of intracellular calcium stores was not involved in calcium current inhibition under these experimental conditions. PTX also blocked the L-AP4-induced inhibition of monosynaptic EPSPs evoked by intracellular stimulation of cultured mitral cells. These results suggest that the presynaptic AP4 receptor is a G-protein-coupled glutamate receptor, and that inhibition of calcium influx by a membrane-delimited action of a G-protein may account for L-AP4-induced presynaptic inhibition.
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PMID:L-AP4 inhibits calcium currents and synaptic transmission via a G-protein-coupled glutamate receptor. 131 54

We examined the intracellular signal transduction of two endothelin receptor subtypes (ETA and ETB) by transfection and stable expression of individual receptor cDNAs in Chinese hamster ovary cells. Both receptors showed a rapid and marked stimulation of phosphatidylinositol hydrolysis and arachidonic acid release in response to agonist interaction. The two receptors, however, exhibited different responses in the cyclic AMP transduction cascades. ETA mediated the accumulation of cyclic AMP formation, whereas ETB displayed an inhibitory action on the forskolin-stimulated cyclic AMP accumulation. In both receptors, the responses of phosphatidylinositol hydrolysis, arachidonic acid release, and cyclic AMP formation were induced in complete agreement with the endothelin-binding selectivity of each receptor subtype. Endothelin, added together with GTP, activated the adenylate cyclase activity in membrane preparations of ETA-expressing cells, indicating the direct linkage of ETA to the adenylate cyclase system. Pertussis toxin treatment of ETA-expressing cells resulted in partial inhibition of the endothelin-induced cyclic AMP accumulation, whereas the same treatment of ETB-expressing cells completely abolished the endothelin-induced inhibition of cyclic AMP formation. Thus, the two endothelin receptor subtypes are coupled to multiple but distinct signal transduction cascades through different G proteins.
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PMID:Coupling of two endothelin receptor subtypes to differing signal transduction in transfected Chinese hamster ovary cells. 131 97


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