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)

We have previously reported the selective amplification of several rat striatal cDNA sequences that encode guanine nucleotide-binding regulatory protein (G protein)-coupled receptors. One of these sequences (R226) exhibited high sequence identity (58%) with the two previously cloned adenosine receptors. A full-length cDNA clone for R226 has been isolated from a rat brain cDNA library. The cDNA clone encodes a protein of 320 amino acids that can be organized into seven transmembrane stretches. R226 has been expressed in COS-7 and CHO cells and membranes from the transfected cells were screened with adenosine receptor radioligands. R226 could bind the nonselective adenosine agonist tritiated N-ethyladenosine 5'-uronic acid ([3H]NECA) and A1-selective agonist radioiodinated N6-2-(4-amino-3-iodophenyl)-ethyladenosine ([125I]APNEA) but not A1-selective antagonists tritiated 1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) and 8-(4-[([[(2-aminoethyl)amino]carbonyl]methyl)oxy]-phenyl)-1, 3-dipropylxanthine ([3H]XAC) or the A2-selective agonist ligands tritiated 2-[4-(2-carboxyethyl)phenyl]ethyl-amino 5'-N-ethylcarboxamidoadenosine ([3H]CGS21680) and radioiodinated 2-[4-([2-[(4-aminophenyl)methylcarbonylamino] ethylaminocarbonyl]ethyl)phenyl]ethylamino 5'-N-ethylcarboxamidoadenosine. Extensive characterization with [125I]APNEA showed that R226 binds [125I]APNEA with high affinity (Kd = 15.5 +/- 2.4 nM) and the specific [125I]APNEA binding could be inhibited by adenosine ligands with a potency order of (R)-N6-phenyl-2-propyladenosine (R-PIA) = NECA greater than S-PIA greater than adenosine greater than ATP = ADP but not by antagonists XAC, isobutylmethylxanthine, and DPCPX. In R226 stably transfected CHO cells, adenosine agonists R-PIA, NECA, and CGS21680 inhibited by 40-50% the forskolin-stimulated cAMP accumulation through a pertussis toxin-sensitive G protein with an EC50 of 18 +/- 5.6 nM, 23 +/- 3.5 nM, and 144 +/- 34 nM, respectively. Based on these observations we conclude that R226 encodes an adenosine receptor with non-A1 and non-A2 specificity, and we thus name it the A3 adenosine receptor. mRNA analyses revealed that the highest expression of R226 was in the testis and low-level mRNAs were also found in the lung, kidneys, heart, and some parts of the central nervous system such as cortex, striatum, and olfactory bulb. The high-expression level of the A3 receptor in the testis suggests a possible role for adenosine in reproduction.
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PMID:Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. 132 36

The effects of adenosine receptor agonists and antagonists on field-stimulated release of radioactivity from superfused guinea-pig papillary muscles preincubated with [3H] noradrenaline were studied. N6-cyclopentyladenosine (CPA), N6-(R-phenylisopropyl)-adenosine, and 5'-N-ethylcarboxamidoadenosine caused concentration-dependent inhibition of evoked overflow with a rank order of potency typical for interaction of the compounds with the A1-subtype of adenosine receptors. Maximum inhibition was 80%. The A1-selective antagonist 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX) induced a rightward shift of the concentration-response curve for CPA with a pA2 of 8.35. However, DPCPX per se had no effect on stimulation-evoked tritium overflow. On the other hand, in the presence of 4-nitrobenzylthioinosine (2 mumol/l) and deoxycoformycin (1 mumol/l), inhibitors of adenosine uptake and deamination, respectively, DPCPX produced a concentration-dependent increase in overflow with a pD2 of 8.1. Pretreatment of the animals with pertussis toxin caused a substantial reduction in the activity of toxin-sensitive G proteins, as indicated by a lack of [32P]ADP ribosylation in a ventricular membrane preparation. Nevertheless, the inhibitory effect of the adenosine receptor agonists on stimulus-evoked overflow remained unaffected. These results are compatible with the existence of inhibitory prejunctional adenosine receptors in guinea-pig papillary muscle, which appear to be coupled to a pertussis toxin-insensitive G protein. The role of endogenous adenosine in occupying these receptors seems minimal under basal conditions.
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PMID:Adenosine receptors mediate a pertussis toxin-insensitive prejunctional inhibition of noradrenaline release on a papillary muscle model. 190 20

Human rTNF-alpha (greater than or equal to U/ml) decreased PMN nondirected and directed migration to FMLP to approximately 50% of control. Adenosine (100 microM) almost completely restored hrTNF-inhibited migration (nondirected from 54 to 92% and directed migration to from 54 to 93% of control). The lowest concentration of adenosine that restored hrTNF-inhibited migration was 3 microM, and the adenosine analogue, 5'-(N-cyclopropyl)-carboxamido-adenosine (CPCA) was more potent than adenosine. Although CPCA binds to A2-receptors and stimulates adenylate cyclase, the reversal of hrTNF-inhibited chemotaxis was found to be independent of both PMN cAMP content and binding to A2-receptors, because neither 8-Br-cAMP nor pertussis adenylate cyclase restored hrTNF-inhibited PMN chemotaxis and the A2-receptor antagonist, 1,3-dipropyl-7-methylxanthine decreased CPCA stimulated cAMP but enhanced CPCA-restoration of hrTNF-inhibited chemotaxis. The effect of adenosine could be augmented by inhibition of adenosine uptake and decreased by adenosine deamination. Pentoxifylline, (3,7 dimethyl-1-[5 oxo-hexyl] xanthine), like adenosine also restored PMN chemotaxis inhibited by hrTNF. The adenosine receptor antagonist, 1,3-dipropyl-8(phenyl-p-acrylate)-xanthine (BW A1433U), decreased restoration of hrTNF-inhibited chemotaxis by CPCA or pentoxifylline. Thus, the inhibitory effect of hrTNF on PMN migration can be counteracted by adenosine, CPCA, pentoxifylline, and compounds that increase adenosine availability to the surface of the PMN. Inasmuch as an A1-selective agonist N6-cyclopentyladenosine was less active, and the action of the A2-selective agonist CPCA was enhanced by an A2-receptor antagonist, we hypothesize that neither A1 or A2 receptors are involved in adenosine restoration of hrTNF-inhibited chemotaxis. Further, increased cAMP, an A2-regulated event, does not cause the effect, and adenosine restoration of hrTNF-inhibited migration does not appear to be mediated by changes in PMN [F-actin], FMLP receptor expression, or cytosolic calcium. Hence, the restoration of hrTNF-inhibited chemotaxis is controlled by a novel cyclic AMP-independent action on the PMN surface.
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PMID:Adenosine and related compounds counteract tumor necrosis factor-alpha inhibition of neutrophil migration: implication of a novel cyclic AMP-independent action on the cell surface. 216 64

The effects of adenosine on gastrin release were studied in enzymatically dispersed canine antral cells after 24-36 h in primary culture. We found two contrasting actions for adenosine: inhibition of forskolin-stimulated gastrin release and potentiation of bombesin-stimulated gastrin release. These actions appeared to be mediated by A1 and A2 receptors, respectively. Forskolin-stimulated gastrin release was reduced by adenosine and the A1-selective agonist N6-(L-2-phenylisopropyl)adenosine (L-PIA) but not by the A2-selective agonist 2-phenylaminoadenosine (CV 1808). This inhibition by adenosine was reversed by the preferential A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) as well as by the nonselective adenosine receptor antagonist 8-phenyltheophylline (8-PT). Incubation of the cells with pertussis toxin (200 ng, 8 h) reversed the inhibition by adenosine. In contrast, bombesin stimulation of gastrin release was potentiated by adenosine and CV 1808 but not altered by L-PIA. This effect was enhanced by DPCPX and was not altered by treatment of cells with pertussis toxin. In the absence of exogenous adenosine, 8-PT and DPCPX produced a small increase in basal and stimulated gastrin release. These data suggest dual modulation by adenosine of G-cell function. A1 receptors inhibit adenosine 3,5'-cyclic monophosphate (cAMP)-mediated gastrin release via a pertussis toxin-sensitive mechanism, whereas A2 receptors potentiated the response to cAMP-independent stimuli of gastrin release. Enhancement of gastrin release by adenosine antagonists suggests functional restraint by endogenous adenosine.
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PMID:Dual modulation by adenosine of gastrin release from canine G-cells in primary culture. 222 Oct 65

The adenosine receptors in myocardial membranes of human explanted hearts were labeled with the radiolabeled ligand [3H]DPCPX (1,3-dipropyl-8-cyclopentylxanthine). Agonist competition curves revealed high- and low-affinity states. The addition of guanylyl imidodiphosphate (Gpp (NH)p) converted all receptors to a low-affinity state. The portion of high-affinity states and the influence of guanine nucleotides were most pronounced at 22 degrees C. Only low-affinity states could be detected in pertussis toxin-treated membranes. It is concluded that adenosine receptors in the human ventricle couple via a G protein sensitive to pertussis-toxin. Alterations of the coupling of adenosine receptors might have a pathophysiological role in dilated cardiomyopathy in which pertussis toxin substrates are increased.
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PMID:Coupling of adenosine receptors to a pertussis toxin-sensitive G protein in the human heart. 251 Oct 34

Studies were performed to determine the primary signal transduction mechanism that mediates adenosine stimulation of electrogenic sodium transport in renal epithelial cells. Experiments were performed on cultured amphibian A6 cells with an adenosine analogue that preferentially binds to the A1 receptor, cyclohexyladenosine (CHA). Sodium transport was assessed by the equivalent short circuit current (Ieq). CHA was found to stimulate Ieq via activation of an A1 receptor because (1) the threshold concentration was 1 nM compared to that of 10 microM for the specific A2 agonist CGS21680, (2) CHA inhibited vasopressin (AVP)-stimulated cAMP production by a pertussis toxin-sensitive mechanism, and (3) the action of CHA was inhibited by the A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). CHA increased intracellular Ca2+ ([Ca2+]i) and stimulated phosphoinositide turnover at concentrations that increased Ieq and in a time course that paralleled the increase in Ieq. Ion transport was stimulated by a Ca(2+)-dependent mechanism because the CHA induced increase in Ieq was inhibited by chelating [Ca2+]i with 5,5'dimethyl BAPTA in a dose-dependent manner, with a Ki of approximately 10 microM. The increase in Ieq was also dose-dependently inhibited by the specific PKC inhibitors dihydroxychlorpromazine and chelerythrine, and by trifluoperazine which inhibits PKC and calmodulin. Further studies indicated that CHA-stimulated Ieq was independent of cAMP generation because CHA did not induce an increase in cAMP accumulation parallel to the increase in Ieq in a dose-response analysis, and the adenylate cyclase inhibitor 2',5' dideoxy-adenosine (DDA) did not affect the CHA-induced increase in Ieq.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine stimulation of Na+ transport is mediated by an A1 receptor and a [Ca2+]i-dependent mechanism. 764 26

The properties of the K+ channel activated by acetylcholine (ACh) and adenosine (Ado) were examined in single ferret ventricular myocytes using patch-clamp techniques. In the whole-cell configuration, ACh and Ado induced an inwardly rectifying K+ current and shortened the action potential duration. The effect of ACh was blocked by atropine, while the Ado effect was interrupted by 8-cyclopentyl,1,2-dipropyl xanthine, a specific Ado A1 receptor antagonist. In cell-attached recordings, ACh and Ado added to the pipette solution activated a single population of inwardly rectifying K+ channels, distinct from the iK1 channel. The channel had a slope conductance of approximately 40 pS in symmetrical 150 mM K+ solutions and a mean open time of 0.8 ms. Excision of the patch into the inside-out patch configuration in guanosine triphosphate (GTP)-free solution abolished the channel activity. The channel was reversibly reactivated by adding GTP to the intracellular side of the patch. GTP gamma S activated the channel irreversibly. When the inside-out patch was treated with the A protomer of pertussis toxin (PTX), intracellular GTP no longer activated the K+ channel. The results show that ferret ventricular myocytes possess a K+ channel activated by both muscarinic and Ado A1 receptors. Its electrophysiological properties and the gating by a PTX-sensitive G protein in a membrane-delimited fashion are identical with those of the muscarinic K+ channels in nodal and atrial tissues of other species. In conclusion, the G protein-gated muscarinic K+ channel is expressed in ferret ventricular myocardium and may underlie the direct negative inotropism of ACh and Ado in this tissue.
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PMID:Acetylcholine and adenosine activate the G protein-gated muscarinic K+ channel in ferret ventricular myocytes. 767 19

Release of substance P-like immunoreactivity (SP-LI) from dissociated enteric ganglia and the receptor-mediated prejunctional inhibition of this release were investigated with the use of a perifusion technique. SP-LI release was evoked by elevated extracellular K+ concentration and was inhibited, in a graded manner, by N6-cyclopentyl adenosine (CPA), an adenosine analogue with selectivity for adenosine A1 receptors. Similar inhibition of SP-LI release was obtained with 5-hydroxytryptamine (5-HT); incrementing concentrations, however, yielded a biphasic concentration-response relationship. The selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentyl-xanthine abolished the inhibition due to CPA, whereas the inhibitory action of 5-HT was sensitive to the 5-HT1A-selective antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine hydrobromide. Inhibition due to both agonists was insensitive to blockade by tetrodotoxin, suggesting a prejunctional locus for both adenosine and 5-HT1A receptors on the tachykininergic nerve endings. Pretreatment of ganglia with pertussis toxin had no effect on CPA-mediated inhibition of SP-LI release, whereas 5-HT-mediated inhibition was abolished. The findings demonstrate that adenosine and 5-HT receptors on enteric nerve endings are coupled to inhibition of tachykinin release through distinct mechanisms, putatively distinct G proteins.
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PMID:Adenosine and 5-HT inhibit substance P release from nerve endings in myenteric ganglia by distinct mechanisms. 768 28

The aim of the present study was to elucidate the question of whether cardiomyocytes possess stimulatory adenylyl cyclase-coupled A2-adenosine receptors and whether these receptors modify contractility. In isolated electrically driven ventricular cardiomyocytes from guinea-pig hearts the effects of the A2-adenosine receptor agonist 2-[(p-2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamide-adenos ine (CGS 21680C) alone and in the presence of isoprenaline on cAMP content and contractile response were investigated. In addition, we characterized these effects with selective A1- and A2-adenosine receptor antagonists [1,3-dipropyl-8-cyclopentylxanthine, DPCPX and 9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4-triazolo-(1,5-c)quinazolin++ +-5-imine, CGS 15943A, respectively]. To investigate the signal transduction pathway, the influence of pertussis toxin, known to inhibit signal transducing GTP-binding proteins (Gi/o-proteins), on these effects was studied. CGS 21680C alone and in the presence of isoprenaline increased cAMP content concentration-dependently (0.1 nmol/l-10 mumol/l) to maximally 154% of control and 137% of isoprenaline value, respectively. In the presence of the A1-adenosine receptor antagonist DPCPX (0.3 mumol/l) or after pertussis toxin-pretreatment (18 micrograms/kg i.v. 24-26 h) the cAMP increase was further elevated. The A2-adenosine receptor antagonist CGS 15943A (0.01 mumol/l) abolished these effects, indicating that these effects are mediated by A2-adenosine receptors. The elevation in cAMP content was not accompanied by an increase in contractile response. However, in the presence of isoprenaline CGS 21680C reduced contractile response to 62% of the isoprenaline value. The A1-adenosine receptor antagonist DPCPX abolished the decrease in contractility, whereas the A2-adenosine receptor antagonist CGS 15943A did not effect contractility. Thus the reduction in contractility is mediated via cAMP-decreasing A1-adenosine receptors. The results provide evidence for the coexistence of cAMP-reducing A1- and cAMP-elevating A2-adenosine receptors on ventricular cardiomyocytes. Only stimulation of A1-adenosine receptors leads to a subsequent reduction in contractile response, whereas A2-adenosine receptors do not affect contractility.
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PMID:Pharmacological characterization of A2-adenosine receptors in guinea-pig ventricular cardiomyocytes. 802 23

Adenosine A1 receptors and alpha 2-adrenoceptors are both potent inhibitors of adipocyte lipolysis when activated by their agonists. The aim of this work was to compare the coupling of these receptors to the Gi-proteins in hamster adipocytes. The adenosine A1 receptor was characterized with the antagonist [3H]dipropyl-cyclopentyl-xanthine ([3H]DPCPX) and the agonist [3H](-)-phenylisopropyladenosine ([3H]PIA). It was demonstrated by [32P]ADP-ribosylation with pertussis toxin and immunoblotting that Gi1, Gi2 and Gi3 are expressed in hamster adipocytes. Partial ADP-ribosylation of Gi-proteins by pertussis toxin, acting on the intact cells or on the adipocyte membranes, demonstrated that the adenosine A1 receptor was less sensitive to the disappearance of functional Gi-proteins than the alpha 2-adrenoceptor. These results are in accordance with the weak sensitivity of the binding of the agonist [3H]PIA to guanine nucleotides and seem to confirm that the adenosine A1 receptor is strongly and differently coupled than the alpha 2-adrenoceptor to the Gi-proteins in hamster adipocyte membranes.
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PMID:Coupling of inhibitory receptors with Gi-proteins in hamster adipocytes: comparison between adenosine A1 receptor and alpha 2-adrenoceptor. 805 Apr 82


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