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)

Adenine nucleotides displace the binding of the selective adenosine A-1 receptor ligand [3H]cyclopentyladenosine (CPA) to rat brain membranes in a concentration-dependent manner, with the rank order of activity being ATP greater than ADP greater than AMP. Binding was also displaced by GTP, ITP, adenylylimidodiphosphate (AppNHp), 2-methylthioATP, and the beta-gamma-methylene isostere of ATP, but was unaffected by the alpha-beta-methylene isosteres of ADP and ATP, and UTP. At ATP concentrations greater than 100 microM, the inhibitory effects on CPA binding were reversed, until at 2 mM ATP, specific binding of CPA was identical to that seen in controls. Concentrations of ATP greater than 10 mM totally inhibited specific binding. Inclusion of the catabolic enzyme adenosine deaminase in the incubation medium abolished the inhibitory effects of ATP, indicating that these were due to adenosine formation, presumably due to ectonucleotidase activity. The inhibitory effects were also attenuated by the alpha-beta-methylene isostere of ATP, an ectonucleotidase inhibitor. Adenosine deaminase, alpha-beta-methylene ATP (100 microM), and beta-gamma-methylene ATP (100 microM) had no effect on the "stimulatory" phase of binding, although GTP (100 microM) slightly attenuated it. Comparison of the binding of [3H]CPA in the absence and presence of 2 mM ATP by saturation analysis showed that the KD and apparent Bmax values were identical. Examination of the pharmacology of the control and "ATP-dependent" CPA binding sites showed slight changes in binding of adenosine agonists and antagonists. The responses observed with high concentrations of ATP were not observed with GTP, AppNHp, the chelating agents EDTA and EGTA, or inorganic phosphate. The divalent cations Mg2+ and Ca2+ at 10 mM attenuated the stimulatory actions of high (2 mM) concentrations of ATP, whereas EGTA and EDTA (10 mM) enhanced the "stimulatory" actions of ATP. EDTA (10 mM) abolished the inhibitory effects of ATP, indicating a specific dependence on Mg2+ for the inhibitory response. The effects of ATP on [3H]CPA binding were reversible for antagonists but not agonists. The mechanism by which ATP reverses its own inhibitory action on adenosine A-1 radioligand binding is unclear, and from the observed actions of the divalent cations and chelating agents probably does not involve a phosphorylation-dependent process.
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PMID:Effects of purine nucleotides on the binding of [3H]cyclopentyladenosine to adenosine A-1 receptors in rat brain membranes. 308 5

Decreases in the extracellular Ca2+ concentration (delta Ca) elicited by a 20 Hz/10 s orthodromic stimulus train were measured with combined ion sensitive/recording electrodes in the CA1 area of rat hippocampal slices. Addition of the selective adenosine A1-receptor antagonist, DPCPX, or adenosine deaminase increased evoked delta Ca in the synaptic and pyramidal cell soma layer by more than 100%. This was accompanied by an earlier generation of population spikes during the train. It is concluded that physiological adenosine concentrations of about 1 microM exert a depressive tonus on synaptic transmission and frequency potentiation and that this effect is mediated via A1-receptors.
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PMID:Physiological modulation by adenosine: selective blockade of A1-receptors with DPCPX enhances stimulus train-evoked neuronal Ca influx in rat hippocampal slices. 320 95

The effects of adenosine, adenosine deaminase (ADA), and an irreversible ADA inhibitor 2'-deoxycoformycin (DCF) on granulocyte aggregation in response to four different stimuli: the synthetic chemotaxin N-formyl-met-leu-phe (FMLP), zymosan-activated plasma (ZAP), the calcium ionophore A23187, and phorbol myristate acetate (PMA) were studied. Adenosine inhibited granulocyte aggregation in response to 10(-7) mol/L FMLP in a dose-dependent fashion; inhibition in the presence of 1 mumol/L adenosine was 25% +/- 3% (SD) and was 50% (the maximal inhibition observed) with 1 mmol/L adenosine. Quantitatively similar results were obtained when ZAP or A23187 was used as the aggregant but the response to PMA was not affected. ADA not only reversed the inhibition due to adenosine but actually augmented the aggregation to FMLP by 118% +/- 9%. Similar results were obtained with ZAP and A23187 but not with PMA. These effects of ADA depended on its enzymatic activity as they could be blocked by preincubation with DCF. Fluorescent measurement of intracellular calcium in fura-2 loaded granulocyte suspensions established that neither adenosine nor ADA affected subsequent FMLP-stimulated calcium responses. Adenosine, therefore, may inhibit granulocyte responsiveness by blocking signal transduction at a point after calcium entry/mobilization but before activation of protein kinase C. Furthermore, the augmentation of responses seen with ADA suggests that endogenous adenosine may be a physiologic autocrine regulator of granulocyte function.
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PMID:Endogenous and exogenous adenosine inhibit granulocyte aggregation without altering the associated rise in intracellular calcium concentration. 326 May 24

When thymocytes were cultured with adenosine, deoxyadenosine, or deoxyguanosine at 1 mM for 24 h, DNA cleavage at internucleosomal sites with multiples of approximately 180 bp was induced, followed by lactate dehydrogenase release into the medium. In the presence of coformycin, an adenosine deaminase inhibitor, or formycin B, a purine nucleoside phosphorylase inhibitor, DNA cleavage was induced by these nucleosides at concentrations of less than 50 microM. Other purine and pyrimidine ribo- and deoxyribonucleosides did not induce DNA cleavage or LDH release. Because thymocyte nuclei contain a Ca2+,Mg2+-dependent endonuclease, which preferentially cuts DNA in its linker regions, DNA fragmentation induced by the three purine nucleosides was suggested to occur through increased activity of the endonuclease. The DNA cleavage induced by the nucleosides required protein phosphorylation and synthesis, inasmuch as it was inhibited by an inhibitor of protein kinases, H-7, and by an inhibitor of protein synthesis, cycloheximide. The inhibition of DNA cleavage was accompanied by a reduction in lactate dehydrogenase release, suggesting a causal relationship between DNA cleavage and cell death. The DNA cleavage and subsequent cell lysis might be related to the selective thymocyte deletion observed in patients with adenosine deaminase or purine nucleoside phosphorylase deficiency.
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PMID:Adenosine, deoxyadenosine, and deoxyguanosine induce DNA cleavage in mouse thymocytes. 326 57

Extracellular and intracellular recordings from CA1 pyramidal neurones of rats in vitro were used to study the effects of endogenous and exogenously applied adenosine. The adenosine receptor antagonist, caffeine, enhanced the intracellular recorded e.p.s.p.-i.p.s.p. sequence evoked by stimulation of the stratum radiatum which is antagonized by exogenous adenosine. The late, potassium dependent i.p.s.p. was not antagonized. The adenosine uptake inhibitor, nitrobenzylthioinosine (NBTI), mimicked the effects of exogenously applied adenosine. The effects of NBTI and of exogenously applied adenosine were antagonized by caffeine in the same manner. Exposure to adenosine deaminase enhanced the evoked field e.p.s.p. During this enhancement caffeines effects were significantly reduced. In low calcium high magnesium medium which abolishes synaptic activity, adenosine deaminase increased, NBTI decreased cell firing. We conclude that endogenous adenosine, release by a calcium independent mechanism, can exert an inhibitory tone on CA1 neurones in vitro. This is consistent with a role for adenosine as a mediator of negative feedback between the metabolic state and electrophysiological activity of nervous tissue.
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PMID:Endogenous adenosine inhibits hippocampal CA1 neurones: further evidence from extra- and intracellular recording. 341 93

Attempts to identify mechanisms by which calcium antagonists might influence intracellular metabolism have not yet yielded conclusive findings. In this study bepridil, verapamil, nifedipine, and nisoldipine were found to have no influence on the rate of rat heart myosin adenosine triphosphatase or the calcium dependence of myofibrillar adenosine triphosphatase. None of these calcium antagonists alters the rate of reaction of any of the adenine nucleotide catabolic or adenosine salvage enzymes, adenylate kinase, creatine kinase, adenosine kinase, adenosine deaminase, or 5' nucleotidase, in extracts of rat heart. All four compounds, however, reduced, apparently in a non-specific manner, the rate of uptake of adenosine by myocytes isolated from rat heart. It is concluded that calcium antagonists may, through intercalation with the sarcolemmal membrane, inhibit efflux of adenosine formed by catabolism of adenine nucleotides in ischaemic myocytes. This might offer therapeutic advantage since the intracellular concentration of adenosine would thereby be increased, allowing an increased rate of incorporation of adenosine into the adenosine triphosphate pool in reoxygenated myocardium.
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PMID:Calcium antagonists and adenine nucleotide metabolism in rat heart. 349 85

In the guinea-pig stomach fundus strips, set in cascade, amrinone (3 microM to 0.3 mM) induced contractions which were followed by relaxation only at the highest amrinone concentrations tested (30 mM to 0.3 M). Contractions were transient and scarcely related to the drug concentration used, whereas relaxation was the most pronounced and concentration-dependent effect. The transient contraction elicited by amrinone was abolished by scopolamine, indicating activation of cholinergic receptors, but it was unaffected by low temperature or hemicholinium-3. The relaxing effect induced by amrinone was unaffected by low temperature, by the receptor inhibitors used (scopolamine, phenoxybenzamine, propranolol, methysergide, pyrilamine) and by indomethacin. It was potentiated by dipyridamole (0.1 microM) and completely suppressed by tissue pretreatment with adenosine deaminase (10 U/ml). Inhibition of this effect was also obtained by reducing Ca2+ concentration in the perfusion fluid or by pretreating the preparations with verapamil. These results indicate the involvement of endogenous adenosine in the relaxing effect of amrinone and the requirement of Ca2+ influx through plasma membrane for this effect.
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PMID:Amrinone action on guinea-pig isolated stomach fundus. 357 21

In potassium-depolarized guinea-pig left atria treated with isoproterenol, calcium entry blocking activities of adenosine and its potentiating compounds, dipyridamole, lidoflazine and dilazep were studied and compared to verapamil and diltiazem. pA2 values for various drugs were calculated using concentration-response curves for calcium (parallel shift to the right). The order of potency for the calcium entry blocking effect was: verapamil greater than diltiazem greater than adenosine greater than lidoflazine = dilazep greater than dipyridamole. Adenosine caused negative inotropic effects in depolarized left atria. The negative inotropic effect of adenosine was very quick in onset and was potentiated by erythro-6-amino-9(2-hydroxy-3-nonyl)-purine hydrochloride (EHNA), an adenosine deaminase inhibitor, suggesting that adenosine was being degraded. The effect of adenosine was quickly abolished by adenosine deaminase (ADA) and antagonized by 8-phenyltheophylline (8-PT), suggesting that the action of adenosine was most likely through the surface membrane receptor sites. The negative inotropic effects of dilazep and dipyridamole were only partially reversed by ADA and 8-PT, while that of lidoflazine was not affected by these agents. These findings suggest that the mechanism(s) of negative intotropic effect of lidoflazine was different from that of dilazep and dipyridamole. These data suggest that the negative intropic effect of dilazep is most likely due to a direct calcium entry blocking effect and in part due to its adenosine potentiating effect. However, the calcium entry blocking effect of lidoflazine is independent of adenosine.
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PMID:Calcium entry blocking activity of dilazep and other adenosine potentiating compounds in guinea-pig atria. 395 77

Adenosine increases the activity of tyrosine 3-monooxygenase in intact pheochromocytoma cells. The effect of adenosine is not dependent upon extracellular Ca2+, and is not accompanied by an increase in catecholamine secretion from the cells. Adenosine deaminase decreases the basal activity of tyrosine 3-monooxygenase, and almost completely abolishes the activation of this enzyme by adenosine. In cells treated with adenosine deaminase, 2-chloroadenosine causes a 2- to 5-fold increase in tyrosine 3-monooxygenase activity. 2-Chloroadenosine produces half-maximal activation at a concentration of 0.1 microM, and maximal activation at 10 microM. Incubation of cells with 2-chloroadenosine produces a stable activation of tyrosine 3-monooxygenase, as measured in vitro. Finally, 3-chloroadenosine increases the content of cAMP in pheochromocytoma cells, and increases the incorporation of 3H into cAMP in cells that have been preincubated with [3H]adenine. This rise in cAMP presumably mediates the activation of tyrosine 3-monooxygenase by 2-chloroadenosine. Adenosine appears to be an endogenous regulator of tyrosine 3-monooxygenase activity in pheochromocytoma cells.
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PMID:Activation of tyrosine 3-monooxygenase in pheochromocytoma cells by adenosine. 610 63

Adenosine and its analogs depress the firing of neurons in various brain regions. The primary mode of action of adenosine in exerting this action appears to be the depression of calcium entry, thus decreasing presynaptic neurotransmitter release. Adenosine uptake inhibitors and adenosine deaminase inhibitors potentiate the depressant actions of adenosine. Caffeine and theophylline, methylxanthines, antagonize these actions. Adenosine is therefore likely to be released and to exert an ongoing modulation of the neuron excitability in the intact brain. Adenosine uptake by nerve terminals appears to be important in regulating the extracellular concentration of adenosine and thus of adenosine's action. A number of groups of centrally active sedative, anxiolytic and anticonvulsant drugs inhibit adenosine uptake by brain synaptosomal preparations. It is proposed that these agents exert their sedative effects by inhibiting adenosine uptake and thus potentiating depressant actions by locally released adenosine on neuronal activity.
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PMID:Adenosine mediates sedative action of various centrally active drugs. 613 Apr 65


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