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:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular purine nucleosides and nucleotides in micromolar concentrations stimulate proliferation of a variety of cell types in vitro and in vivo. As well they act synergistically with NGF to stimulate neurite outgrowth from PC12 cells. A variety of purine nucleosides and deoxyribonucleosides promote cell proliferation and increase intracellular cAMP. Their activities are inhibited by adenosine A2 receptor antagonists. Only adenosine interacts with the A2 receptor. We propose that the other nucleosides and deoxyribonucleosides inhibit extracellular adenosine deaminase, thereby increasing the extracellular concentration of adenosine. The nucleotides apparently act by stimulating P2y receptors coupled to inositol phosphate metabolism. We propose that the nucleosides and nucleotides act synergistically with other growth factors because each has distinct but complementary second messenger systems. If our hypotheses are correct, it should prove possible to modulate the growth and morphogenesis in several cell types using drugs that inhibit or stimulate adenosine A2 or purine P2y receptor agonists or the second messenger systems coupled to these receptors.
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PMID:Purinergic stimulation of cell division and differentiation: mechanisms and pharmacological implications. 162 96

The cDNA of an unidentified recently cloned G protein-coupled receptor, RDC8, has been expressed in Y1 adrenal cells, in dog thyrocytes in primary culture and in Xenopus oocytes. In all these systems this resulted in the activation of adenylyl cyclase and of the cyclic AMP cascade in the absence of any added external signal. However, this physiologically constitutive activator was inhibited by adenosine deaminase and by inhibitors of the adenosine A2 receptor. Cos 7 cells transfected with RDC8 cDNA constructs acquired binding characteristics of an adenosine A2 receptor. Moreover, RDC8 mRNA and adenosine A2 receptors display a very similar distribution in the brain. RDC8 therefore codes for an A2 adenosine receptor. Whether the physiologically constitutive activation of this receptor is entirely explained by endogeneously produced adenosine is as yet unknown.
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PMID:RDC8 codes for an adenosine A2 receptor with physiological constitutive activity. 212 16

In summary, intermittent, low dose methotrexate treatment is: 1.) antiinflammatory in the murine air pouch model of inflammation; 2.) selectively increases intracellular AICAR concentration; 3.) increases adenosine concentration in an inflammatory exudate; and, 4.) inhibits leukocyte accumulation at an inflamed site by a mechanism that is specifically reversed by adenosine deaminase and the adenosine A2 receptor antagonist DMPX but not the A1 antagonist DPCPX. In conclusion, we have demonstrated a novel mechanism for the antiinflammatory action of methotrexate; methotrexate is a nonsteroidal antiinflammatory agent that acts by promoting the release of adenosine which engages A2 receptors on inflammatory cells.
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PMID:The antiinflammatory effects of methotrexate are mediated by adenosine. 766 Sep 40

Methotrexate, a folate antagonist, is a potent antiinflammatory agent when used weekly in low concentrations. We examined the hypothesis that the antiphlogistic effects of methotrexate result from its capacity to promote intracellular accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) that, under conditions of cell injury, increases local adenosine release. We now present the first evidence to establish this mechanism of action in an in vivo model of inflammation, the murine air pouch model. Mice were injected intraperitoneally with either methotrexate or saline for 3-4 wk during induction of air pouches. Pharmacologically relevant doses of methotrexate increased splenocyte AICAR content, raised adenosine concentrations in exudates from carrageenan-inflamed air pouches, and markedly inhibited leukocyte accumulation in inflamed air pouches. The methotrexate-mediated reduction in leukocyte accumulation was partially reversed by injection of adenosine deaminase (ADA) into the air pouch, completely reversed by a specific adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), but not affected by an adenosine A1 receptor antagonist, 8-cyclopentyl-dipropylxanthine. Neither ADA nor DMPX affected leukocyte accumulation in the inflamed pouches of animals treated with either saline or the potent antiinflammatory steroid dexamethasone. These results indicate that methotrexate is a nonsteroidal antiinflammatory agent, the antiphlogistic action of which is due to increased adenosine release at inflamed sites.
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PMID:The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. 825 24

1. This paper describes aspects of the functional antagonism between the responses mediated by activated alpha 1-adrenoceptors and adenosine A2 receptors in the adventitia- and endothelium-denuded aorta of the rabbit. 2. Adenosine A2 receptor agonists relaxed aortic rings pre-contracted with phenylephrine. The relaxation response was agonist concentration-dependent and saturable. The respective contractile and relaxation responses were stable, reproducible, and reversible. 3. Increasing the phenylephrine concentration caused a progressive attenuation of the action of adenosine A2 receptor agonists, consisting of a decreased maximal response and a dextral shift of the adenosine agonist concentration-response curve. This functional antagonism could be completely reversed upon removal of adenosine by either the addition of adenosine deaminase or by wash-out of the adenosine agonist from the tissue. The relaxation response to the adenosine A2 receptor partial agonists, N6-cyclohexyladenosine and R-(-)-N6-(2-phenylisopropyl)adenosine, was abolished at higher phenylephrine concentrations (e.g. 30 EC50). 4. A 1000 fold increase in the adenosine concentration was required to shift the value of the EC50 of phenylephrine six fold, while a similar increase in the value of the EC50 of adenosine could be elicited by only a 32 fold increase in the phenylephrine concentration. A 30 fold increase in the phenylephrine concentration shifted the value of the EC50 of 5'-N-ethylcarboxamidoadenosine four fold. 5. Analysis of the functional antagonism between the responses mediated by these receptors using the Black & Leff (1983) operational model of agonism allowed for the estimation of the agonist dissociation constant, KA, and the apparent efficacy, tau, for both phenylephrine and adenosine A2 receptor agonists. Increasing the concentration of phenylephrine reduced the value of tau for adenosine agonists in a concentration-dependent and saturable manner. Similarly, increasing the concentration of adenosine reduced the value of tau for phenylephrine in a concentration-dependent and saturable manner. The phenylephrine KA value obtained by the method of functional antagonism (1.9 microM) was similar to that obtained by the receptor inactivation method (2.1 microM). 6. Partial occlusion of the alpha 1-adrenoceptor by the alkylating agent, dibenamine, demonstrated that the magnitude of the adenosine A2 receptor-mediated relaxation was inversely proportional to the number of functional alpha 1-adrenoceptors. 7. It is concluded that the magnitude of functional antagonism is proportional to the stimulus elicited through either receptor. We propose that this tissue preparation and pair of receptors is a good model to study quantitative aspects of functional antagonism between activated receptors.
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PMID:Interactions between responses mediated by activation of adenosine A2 receptors and alpha 1-adrenoceptors in the rabbit isolated aorta. 839 86

The anti-inflammatory mechanism of sulfasalazine is not well understood. It has recently been shown that sulfasalazine inhibits 5-aminoimidazole-4-carboxamidoribonucleotide (AICAR) transformylase, an enzyme involved in de novo purine biosynthesis. We recently demonstrated that methotrexate promotes intracellular AICAR accumulation, thereby increasing adenosine release and diminishing inflammation, so we tested the hypothesis that sulfasalazine similarly promotes intracellular AICAR accumulation. We studied adenosine release and the state of inflammation in in vitro and in vivo models of the inflammatory process. The adhesion of stimulated neutrophils (FMLP) to endothelial cells preincubated with sulfasalazine was inhibited in a dose-dependent manner. Elimination of extracellular adenosine by addition of adenosine deaminase or inhibition of adenosine by the adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) completely reversed the anti-inflammatory effect of sulfasalazine (at concentrations <1 microM in this in vitro model. To determine whether this phenomenon was relevant to inhibition of inflammation in vivo, we studied the effect of sulfasalazine (100 mg/kg/day by gastric gavage for 3 days) on leukocyte accumulation in the murine air pouch model of inflammation. Treatment with sulfasalazine markedly decreased the number of leukocytes that accumulated in the inflamed (carrageenan, 2 mg/ml) air pouch. Injection of either adenosine deaminase or DMPX, but not the A1 receptor antagonist 8-cyclopentyl-dipropylxanthine, significantly reversed the anti-inflammatory effects of sulfasalazine treatment. Sulfasalazine increased the exudate adenosine concentration from 127 +/- 64 nM to 869 +/- 47 nM. Moreover, sulfasalazine treatment promoted a marked increase in splenocyte AICAR concentration from 35 +/- 6 to 96 +/- 3 pmols/10(6) splenocytes, which is consistent with the in vitro observation that sulfasalazine inhibits AICAR transformylase. These results indicate that sulfasalazine, like methotrexate, enhances adenosine release at an inflamed site and that adenosine diminishes inflammation via occupancy of A2 receptors on inflammatory cells. Our studies provide evidence that sulfasalazine and methotrexate may be described as a newly recognized family of anti-inflammatory agents that share the property of using adenosine as an antagonist of inflammation.
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PMID:The anti-inflammatory mechanism of sulfasalazine is related to adenosine release at inflamed sites. 859 47

1. Engagement of adenosine A2 receptors suppresses several leukocyte functions. In the present study, we examined the effect of adenosine on the inhibition of leukotriene B4 (LTB4) synthesis in heparinized human whole blood, pretreated with lipopolysaccharide (LPS) and tumour necrosis factor alpha (TNF-alpha) and stimulated with the chemotactic peptide, N-formyl-Met-Leu-Phe (FMLP). 2. The FMLP-induced synthesis of LTB4 in whole blood pretreated with LPS and TNF-alpha was dose-dependently inhibited by adenosine analogues in the following order of potency; 5'(N-ethyl)carboxamidoadenosine (NECA) approximately equal to CGS 21680 > 2-Cl-adenosine > N6-cyclopentyladenosine (CPA), indicating the involvement of the adenosine A2 receptor subtype. The IC50 values for NECA, CGS 21680, 2-Cl-adenosine, and CPA were 6 nM, 9 nM, 180 nM, and 990 nM, respectively. 3. Dipyridamole, an agent that blocks the cellular uptake of adenosine by red cells and causes its accumulation in plasma, also inhibited the synthesis of LTB4 in LPS and TNF-alpha-treated whole blood stimulated by FMLP; moreover, this inhibition was reversed upon addition of adenosine deaminase. 4. A highly selective antagonist of the adenosine A2 receptor, 8-(3-chlorostyryl)caffeine (CSC), reversed the inhibition of LTB4 synthesis by 2-Cl-adenosine and dipyridamole in LPS and TNF-alpha-treated whole blood, stimulated by FMLP. 5. LTB4 synthesis in whole blood originates predominantly from neutrophils and to a lesser extent from monocytes. 2-Cl-adenosine also inhibited the synthesis of LTB4 induced by FMLP in these isolated LPS and TNF-alpha-treated cells; however, 2-Cl-adenosine was a more potent inhibitor of LTB4 synthesis in neutrophils than monocytes. 6. The present data demonstrate that adenosine, acting through A2 receptors, exerts a potent inhibitory effect on the synthesis of LTB4 and thus contribute to the understanding of its anti-inflammatory properties.
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PMID:Adenosine A2 receptor-induced inhibition of leukotriene B4 synthesis in whole blood ex vivo. 873 71

Recent studies have demonstrated the inhibitory effect of exogenous adenosine on TNF production. During inflammation endogenous adenosine levels are elevated and may be one of several anti-inflammatory mediators that reduce TNF synthesis. In the present study the authors investigated this role of adenosine in freshly isolated human PBMC. The effect of endogenous adenosine on TNF formation was studied by four different approaches. First, adenosine deaminase was added to LPS-stimulated mononuclear cells. This enzyme specifically deaminates extracellular adenosine to the inactive metabolite inosine. TNF production was augmented from baseline stimulation (LPS alone) of 3.5 +/- 0.4 ng ml-1 -5.2 +/- 0.9 ng ml-1 in the presence of 10 U ml-1 adenosine deaminase. Second, TNF production was determined after stimulation in the presence of dipyridamole, an inhibitor of cellular re-uptake of adenosine which increases extracellular concentrations. TNF synthesis was reduced dose-dependently from 3.1 +/- 0.9 ng ml-1 -1.1 +/- 0.2 ng ml-1 by 10 microM dipyridamole. Third, the adenosine A2 receptor antagonist 8-(3-chlorostyryl)caffeine (100 nM) enhanced TNF synthesis from a baseline of 3.7 +/- 0.5 ng ml-1 -5.5 +/- 0.9 ng ml-1. In contrast, no increase resulted from the addition of 100 nM of the specific A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. Finally, the authors were able to show that suppression of TNF formation by the specific type IV phosphodiesterase inhibitor rolipram can be completely reversed by adenosine deaminase or by the application of the A2 receptor antagonist. The authors conclude that endogenous adenosine controls TNF production. This effect of adenosine may not only have a physiological role but also appears to contribute to the pharmacological inhibition of TNF synthesis by exogenous agents such as the specific type IV phosphodiesterase inhibitor rolipram.
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PMID:Endogenous adenosine curtails lipopolysaccharide-stimulated tumour necrosis factor synthesis. 904 24

1. The effects of selective agonists at group I, II and III metabotropic glutamate receptors (mGluRs) on adenosine A2 receptor-mediated cyclic AMP formation were compared in cross-chopped slices of adult and neonatal (8 days old) rat striatum, in the presence of 1 u ml(-1) adenosine deaminase. 2. The group II selective agonist, (2S,1R,2R,3R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), elicited a potentiation of 5'-N-ethylcarboxamidoadenosine (NECA)-stimulated cyclic AMP production with similar potencies in adult (EC50 value 122 +/- 35 nM) and neonatal (EC50 value 285 +/-6 nM) brain. In contrast, the group I selective agonist (S)-dihydroxyphenylglycine ((S)-DHPG) augmented the NECA cyclic AMP response in neonatal striatum (EC50 value 9 +/- 1 microM), but at a concentration of 100 microM, (S)-DHPG failed to affect the NECA response in adult striatal slices. 3. The potentiation evoked by (S)-DHPG was specific for group I mGluRs as (2S,3S,4S,)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG), a group II antagonist, was ineffective on the (S)-DHPG (100 microM) response at a concentration (500 microM) which reversed a similar augmentation elicited by DCG-IV (300 nM). Furthermore, a protein kinase C inhibitor (Ro 31-8220, 10 microM) markedly reversed the effect of (S)-DHPG without affecting the response to DCG-IV. 4. The mGluR agonist (2S,3S,4S,)-alpha-(carboxycyclopropyl)glycine (L-CCG-I), elicited a greater potentiation of NECA-stimulated cyclic AMP production in neonatal striatum in comparison with that observed in adult rat brain. Moreover, EC50 values obtained from adult and neonatal striatum were 2 +/-1 microM and 9 +/-1 microM, respectively. These differences in potency might reflect co-activation of both group I and group II mGluRs by L-CCG-I in neonatal striatum. 5. Distinct patterns of mGluR expression in various brain areas might account for previous conflicting data on the nature of the mGluR able to evoke such potentiated responses.
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PMID:mGluR-evoked augmentation of receptor-mediated cyclic AMP formation in neonatal and adult rat striatum. 925 2

This study was designed to determine whether theophylline would augment granulocyte apoptosis via a mechanism of adenosine A2A receptor antagonism. A selective adenosine A2 receptor agonist (CGS-21680, 1 microM) exhibited the most efficient potency for decreasing neutrophil apoptosis for 16 h from 63+/-5 to 19+/-4% (P < 0.001); it exerted poor and adverse effects on eosinophil survival. A selective protein kinase A inhibitor KT-5720 (10 microM) reversed the capacity of dibutyryl cAMP but not CGS-21680 to induce an inhibitory effect on neutrophil apoptosis, suggesting that occupancy of adenosine A2 receptors inhibit neutrophil apoptosis by a cAMP-independent mechanism. Theophylline derivatives show the following pattern of potency for inducing neutrophil apoptosis competing with CGS-21680: 8-phenyltheophylline = 8-p-sulfophenyltheophylline > theophylline >> enprofylline. This pattern is consistent with the affinity established for A2A receptors. Theophylline demonstrated an additive effect to that of anti-Fas antibody (CH11, 1 microg/mL) in inducing neutrophil apoptosis, but not to that of adenosine deaminase or KF-17837 (a selective A2 receptor antagonist; 1 microM), suggesting conflicting effects on the receptor antagonism. These findings suggest that theophylline has an immunomodulatory action on neutrophil apoptosis via a mechanism of A2A antagonism.
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PMID:Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. 1077 Feb 86


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