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

In the human T-cell line, Jurkat, the accumulation of cyclic AMP induced by adenosine is enhanced by tumor-promoting phorbol esters, whereas prostaglandin E2 receptor-stimulated cAMP accumulation is antagonized (Nordstedt et al. 1989). In the present study we examine the involvement of pertussis toxin sensitive guanine nucleotide binding proteins (G-proteins) in producing the phorbol ester effects. Pertussis toxin pretreatment of the Jurkat cells invariably caused an ADP ribosylation of two G-proteins that inhibit adenylyl cyclase, tentatively identified as Gi2 and Gi3, using Western blots. Pertussis toxin treatment had little effect on basal cAMP accumulation, but sometimes inhibited, sometimes stimulated agonist and cholera toxin induced cAMP accumulation. The latter effect was not mimicked by the B-oligomer. Irrespective of whether pertussis toxin stimulated or inhibited NECA and cholera toxin-induced cAMP accumulation it could not block the effect of phorbol-12,13-dibutyrate (PDBu). The inhibitory effect of PDBu on prostaglandin E2-induced cAMP accumulation was, however, invariably eliminated by pertussis toxin treatment. In conclusion, activation of protein kinase C by phorbol esters reveals a Gi-mediated prostaglandin E receptor-induced inhibition of adenylate cyclase in addition to the prostaglandin E receptor-mediated stimulation of cAMP accumulation in Jurkat cells. The enhancement of adenosine A2 receptor stimulated cAMP accumulation by PDBu, on the other hand, does not involve a PTX sensitive Gi-protein.
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PMID:Role of a pertussis toxin sensitive G-protein in mediating the effects of phorbol esters on receptor activated cyclic AMP accumulation in Jurkat cells. 166 31

We have previously shown that extracellular ATP acts as a mitogen via protein kinase C (PKC)-dependent and independent pathways (Wang, D., Huang, N., Gonzalez, F.A., and Heppel, L.A. Multiple signal transduction pathways lead to extracellular ATP-stimulated mitogenesis in mammalian cells. I. Involvement of protein kinase C-dependent and independent pathways in the mitogenic response of mammalian cells to extracellular ATP. J. Cell. Physiol., 1991). The present aim was to determine if metabolism of arachidonic acid, resulting in prostaglandin E2 (PGE2) synthesis and elevation of cAMP levels, plays a role in mitogenesis mediated by extracellular ATP. Addition of ATP caused a marked enhancement of cyclic AMP accumulation in 3T3, 3T6, and A431 cells. Aminophylline, an antagonist of the adenosine A2 receptor, had no effect on the accumulation of cyclic AMP elicited by ATP, while it inhibited the action of adenosine. The accumulation of cyclic AMP was concentration dependent, which corresponds to the stimulation of DNA synthesis by ATP. The maximal accumulation was achieved after 45 min, with an initial delay period of about 15 min. That the activation of arachidonic acid metabolism contributed to cyclic AMP accumulation and mitogenesis stimulated by ATP in 3T3, 3T6, and A431 cells was supported by the following observations: (a) extracellular ATP stimulated the release of [3H]arachidonic acid and PGE2 into the medium; (b) inhibition of arachidonic acid release by inhibitors of phospholipase A2 blocked PGE2 production, cyclic AMP accumulation, and DNA synthesis activated by ATP, and this inhibition could be reversed by adding exogenous arachidonic acid; (c) cyclooxygenase inhibitors, such as indomethacin and aspirin, diminished the release of PGE2 and blocked cyclic AMP accumulation as well as [3H]thymidine incorporation in response to ATP; (d) PGE2 was able to restore [3H]thymidine incorporation when added together with ATP in the presence of cyclooxygenase inhibitors; (e) pertussis toxin inhibited ATP-stimulated DNA synthesis in a time- and dose-dependent fashion as well as arachidonic acid release and PGE2 formation. Other evidence for involvement of a pertussis toxin-sensitive G protein(s) in ATP-stimulated DNA synthesis as well as in arachidonic acid release is presented. In A431 cells, the enhancement of arachidonic acid and cyclic AMP accumulation by ATP was partially blocked by PKC down-regulation, implying that the activation of PKC may represent an additional pathway in ATP-stimulated metabolism of arachidonic acid. In all of these studies, ADP and AMP-PNP, but not adenosine, were as active as ATP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Multiple signal transduction pathways lead to extracellular ATP-stimulated mitogenesis in mammalian cells: II. A pathway involving arachidonic acid release, prostaglandin synthesis, and cyclic AMP accumulation. 185 Jul 50

In this study, the regulation of striatal cyclic-3',5'-adenosine monophosphate (cAMP) formation and GABA release by dopamine D1 and metabotropic glutamate receptors (mGluR) was studied in brain slices. In the absence of adenosine A2 receptor blockade, the mGluR agonist, 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) stimulated cAMP accumulation through a pertussis toxin-insensitive mechanism that could be blocked by L-serine-o-phosphate, but not by L(+)-2-amino-3-phosphonopropionic acid. However, in the presence of the adenosine antagonist, 3-isobutyl-1-methylxanthine, 1S,3R-ACPD had no significant effect on basal cAMP, but it inhibited cAMP formation stimulated by the D1 agonist, SKF 38393. This inhibitory response was prevented by pertussis toxin pretreatment and mimicked by L(+)-2-amino-3-phosphonopropionic acid, but it was unaffected by L-serine-o-phosphate. Thus, 1S,3R-ACPD was determined to activate distinct mGluRs in the striatum that mediate either inhibition or activation of cAMP accumulation, with the latter effect being dependent on the activation of adenosine A2 receptors. A potential physiological role for the interaction between the D1 and adenosine-dependent stimulatory metabotropic receptor was sought by examining this interaction on striatal GABA release. SKF 38393 and 1S,3R-ACPD together were found to potentiate striatal GABA release induced by 15 mM K+. The potentiation was blocked by the D1 antagonist, SCH 23390. However, this effect was only partially mimicked by a high concentration of forskolin (100 microM) and was not blocked by L-serine-o-phosphate, thereby suggesting that the stimulatory mGluR does not mediate this potentiation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of striatal cyclic-3',5'-adenosine monophosphate accumulation and GABA release by glutamate metabotropic and dopamine D1 receptors. 747 79

The adenosine A2a receptor inhibition of potassium (15 mM)-evoked GABA release from striatal nerve terminals has been examined. High extracellular calcium concentrations (4 mM) reduced the effect of the A2a receptor agonist CGS-21680 (1 nM). CGS-21680 inhibited GABA release in the presence of the L-type calcium channel blocker nifedipine, which itself inhibited evoked GABA release (by 16 +/- 4%). omega-Conotoxin inhibited the evoked release by 45 +/- 4% and prevented the action of CGS-21680. Forskolin and 8-bromo cyclic AMP both stimulated evoked GABA release at low concentrations, but at higher concentrations they abolished the inhibition by CGS-21680 without affecting the evoked release. The nonselective protein kinase inhibitor H-7 inhibited both the evoked release and the inhibition by CGS-21680, whereas the selective protein kinase A and G inhibitor HA-1004 had no effect on either evoked release or the action of CGS-21680. Pretreatment with pertussis toxin did not affect the A2a receptor-mediated inhibition. Therefore, the effect of A2a receptor stimulation was not mediated by protein kinases A or G but was inhibited by elevated cyclic AMP levels and mimicked by inhibitors of the N-type calcium channel and protein kinase C.
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PMID:Inhibition of striatal GABA release by the adenosine A2a receptor is not mediated by increases in cyclic AMP. 776 61

Whether the opening of ATP-sensitive K+ channels responsible for adenosine A2 receptor-mediated vasodepression involves a pertussis toxin (PTX)-sensitive G protein was investigated in pithed rats. Adenosine and levcromakalim were used as reference substances. The blood pressure of pithed rats was kept elevated with an i.v. infusion of methoxamine. 2-(1-Octynyl)-adenosine (YT-146; 0.1-10 micrograms/kg i.v.), a selective adenosine A2 receptor agonist, produced a dose-dependent and long-lasting decrease in mean blood pressure (MBP) scarcely affecting heart rate (HR). Levcromakalim (0.3-10 micrograms/kg per min i.v. for 20 min) produced a dose-dependent and slowly developing decrease in MBP. The vasodepressor effects of YT-146 and levcromakalim were antagonized by glibenclamide (20 mg/kg i.v.), a blocker of ATP-sensitive K+ channels; the ED50 values for YT-146 and levcromakalim both increased about 2.5-fold. In rats pretreated with PTX (10 micrograms/kg i.v.), in which vagally induced bradycardia was nearly abolished, the vasodepressor effects of YT-146 and levcromakalim were slightly enhanced. Adenosine (0.3-10 mg/kg per min i.v. for 1 min) produced a dose-dependent and long-lasting decrease in MBP accompanied by a transient decrease in HR. The vasodepressor effect of adenosine was antagonized by glibenclamide; the ED50 value for adenosine increased about 3.2-fold, but not after PTX pretreatment. In contrast, the transient bradycardia was antagonized by PTX pretreatment but not by glibenclamide. These results suggest that the opening of ATP-sensitive K+ channels in vascular smooth muscle following stimulation of adenosine A2 receptors by YT-146 and adenosine does not involve a PTX-sensitive G protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Opening of ATP-sensitive K+ channels responsible for adenosine A2 receptor-mediated vasodepression does not involve a pertussis toxin-sensitive G protein. 831 53

The expression and function of stimulatory adenosine A2 receptor on the cardiac myocyte is not well defined. The objective of the present study is to characterize the A2a receptor in adult rat cardiac ventricular myocytes. After selection of an optimal lot of collagenase for myocyte isolation and for consistent measurement of adenosine-mediated responses, the A1-receptor pathway was inactivated by pertussis toxin and by the A1-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine. Effects of the adenosine agonist and antagonist or cardiac myocyte contractile amplitude and on adenosine 3',5'-cyclic monophosphate (cAMP) levels were determined. The A2a-receptor-selective agonist 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoade nos ine (CGS-21680) caused a pronounced stimulation of myocyte contractile amplitude and an increase in the cAMP level, as did the nonselective agonists 5'-(N-ethylcarboxamido) adenosine (NECA) and adenosine. The A2a-receptor-selective antagonist 8-(3-chlorostyryl)caffeine blocked the NECA- and adenosine-induced positive inotropic response. Probing of myocyte RNA with a rat A2a-receptor cDNA demonstrated a 2.6-kb mRNA, corresponding to that encoding the A2a receptor. Together, data from contractile, cAMP, and RNA studies indicate that A2a receptors are expressed and are functionally coupled to stimulation of cAMP accumulation and cardiac contractility in adult rat ventricular myocytes.
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PMID:Characterization of a stimulatory adenosine A2a receptor in adult rat ventricular myocyte. 892 71

Dopamine release is activated by ethanol and addicting drugs, but molecular mechanisms linking dopaminergic signaling to neuronal responses and drinking behavior are poorly understood. We report that dopamine-D2 receptors induce PKA Calpha translocation and increase CRE-regulated gene expression. Ethanol also activates PKA signaling. Subthreshold concentrations of the D2 agonist NPA and ethanol, without effect alone, together cause synergistic PKA translocation and CRE-mediated gene transcription. D2 or adenosine A2 receptor blockade, pertussis toxin, Rp-cAMPS, or overexpression of dominant-negative peptides that sequester betagamma dimers prevent synergy. Importantly, overexpression of a betagamma inhibitor peptide in the nucleus accumbens strikingly reduces sustained alcohol consumption. We propose that synergy of D2 and A2 confers ethanol hypersensitivity and that betagamma dimers are required for voluntary drinking.
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PMID:betagamma Dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption. 1208 72