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)

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

1. This study investigated the effects of acute and chronic ethanol on basal, agonist- and forskolin-stimulated cyclic AMP formation in NG108-15 mouse neuroblastoma x rat glioma hybrid cells, and examined the role of changes in extracellular adenosine concentrations on the effects observed. 2. NG108-15 cells incubated acutely with ethanol (1-200 mM) displayed concentration-dependent increases in basal and iloprost-stimulated (300 nM; a prostanoid IP receptor agonist) cyclic AMP accumulation but a concentration-dependent decrease in forskolin-stimulated (10 microM) accumulation. 3. Cells treated chronically with ethanol (200 mM) for 48 h displayed increases over control in basal, iloprost- (0.001-10 microM) and forskolin (0.01-100 microM)-stimulated cyclic AMP formation. However, chronic ethanol did not affect [3H]-iloprost binding to cell membranes. 4. Inclusion of adenosine deaminase (ADA; 1 unit ml-1) during the incubation period to measure cyclic AMP accumulation completely abolished the increase in basal accumulation following chronic ethanol, but did not affect the increase in iloprost stimulation. On the other hand ADA partially reversed the increase in forskolin stimulation following chronic ethanol, but even in the presence of high concentrations of ADA (5 units ml-1) the forskolin stimulation remained elevated above control. 5. Cells treated chronically with the adenosine receptor agonist 5'-(N-ethylcarboxamido)-adenosine (NECA; 10 microM for 48 h) displayed a reduction in subsequent NECA- and forskolin-stimulated cyclic AMP accumulation, but iloprost stimulation was not affected. ADA included acutely during the incubation period to measure cyclic AMP accumulation abolished the reduction in forskolin but not NECA stimulation produced by the chronic NECA pretreatment. 6. We have previously noted that ethanol inhibits NG108-15 cell proliferation and alters cell morphology.To mimic this, cells were incubated in the absence of foetal calf serum for 48 h. Following this time, basal, iloprost- and forskolin-stimulated cyclic AMP formation was enhanced over that in cells grown in the presence of serum.7. These results indicate that chronic ethanol enhances cyclic AMP formation in intact NG108-15 cells by more than one mechanism: one involves increased extracellular adenosine concentrations and the other a change in the transduction system beyond the receptor, possibly involving the adenylyl cyclase enzyme. Furthermore the ethanol-induced changes in cyclic AMP accumulation may relate to alterations in NG108-15 cell growth and development.
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PMID:Effects of acute and chronic ethanol on cyclic AMP accumulation in NG108-15 cells: differential dependence of changes on extracellular adenosine. 754 91

1. Adenosine is known to stimulate capillary outgrowth and endothelial cell proliferation, but the underlying mechanism has not been identified. In order to identify the receptor subtype involved, the effects of adenosine receptor agonists and antagonists on human umbilical vein endothelial cell (HUVEC) proliferation were investigated. 2. Raising intracellular adenosine levels by use of the adenosine transport inhibitor, 4-nitrobenzylthioinosine (NBMPR) did not affect cell growth. This observation suggests that stimulation of an extracellular adenosine receptor generates the mitogenic signal. 3. In the presence of adenosine deaminase (ADA), which was used to remove adenosine present in the culture medium, the adenosine receptor agonists N-ethylcarboxamidoadenosine (NECA, non-selective) and CGS21680 (A2A-receptor-selective) stimulated [3H]-thymidine incorporation with a half-maximum effect at about 10 nM, while N6-cyclopentyladenosine (CPA, A1-selective) was about 100 fold less potent. The adenosine receptor antagonist, xanthine amine congener (XAC) produced a concentration-dependent decrease in endothelial cell proliferation with a half-maximum effect at about 10 nM. Hence, stimulation of an endothelial A2A-adenosine receptor seems responsible for the mitogenic signal. 4. In the presence of ADA, isoprenaline is also able to stimulate [3H]-thymidine incorporation with a half maximal effect of about 3 nM, an effect, which is reversed by the highly beta 2-selective antagonist, ICI 118,551. In the absence of ADA, isoprenaline exerts only a minor stimulatory effect. Combination of A2A adenosine and beta 2-adrenoceptor agonists did not further enhance [3H]-thymidine incorporation when compared to the sole addition of each agonist. We therefore conclude that both receptors stimulate endothelial cell proliferation via a common signal transduction pathway. 5. Both receptors are coupled to stimulation of adenylyl cyclase via the stimulatory G protein G8.However, direct activation of downstream effectors in the cyclic AMP-signalling cascade (G8 with cholera toxin, adenylyl cyclase with forskolin, protein kinase A with 8Br-cyclic AMP) not only failed to mimic the action of receptor-activation, but even reduced cell proliferation.6. Similarly, pertussis toxin-treatment which inactivated the Gi 2 protein present in HUVEC and thus inhibited cell proliferation per se, did not impair the ability of A2A-receptor agonists to stimulate cell proliferation. This suggests that the A2A-adenosine and beta2-adrenoceptor-mediated stimulation of endothelial cell proliferation occurs via a mechanism that is independent of G8 and Gi.
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PMID:Stimulation of human umbilical vein endothelial cell proliferation by A2-adenosine and beta 2-adrenoceptors. 759 25

Adenosine 3',5'-cyclic monophosphate (cAMP), accumulated in the presence of adenosine, was measured in medullary portions of mouse thick ascending limbs of Henle's loop, suspended either in classic extracellular buffer or in the presence of added NaCl. Under control conditions (140 mmol/l NaCl), adenosine (< 10(-5) mol/l) and N6-cyclohexyladenosine, an A1 adenosine receptor agonist, inhibit the cAMP accumulation induced by arginine vasopressin (AVP). On the other hand, high concentrations of adenosine and CGS-21680, an A2 adenosine receptor agonist, stimulate cAMP formation. Addition of NaCl (+300 mmol/l) to extracellular buffer stimulates the release of endogenous adenosine. It also enhances A2 receptor-induced cAMP accumulation but suppresses A1 receptor-mediated inhibition of adenylyl cyclase. This hypertonic NaCl medium also potentiates the stimulatory action of AVP on adenylyl cyclase. The modifications of tubular responses to both AVP and A1 and A2 agonists, brought about by hypertonic NaCl, were all inhibited by adenosine deaminase, thereby demonstrating the involvement of endogenous adenosine. Adenosine, the release and the effects of which are modulated by hypertonic NaCl, thus appears to act as an endogenous physiological modulator of kidney medulla function.
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PMID:Hypertonic NaCl enhances adenosine release and hormonal cAMP production in mouse thick ascending limb. 763 23

Brief exposure of primary cultures of hepatocytes to ethanol had a biphasic effect on glucagon receptor-dependent cyclic AMP (cAMP) production: 25-50 mM ethanol decreased cAMP levels, whereas treatment with 100-200 mM ethanol increased cAMP. This biphasic effect was also observed after pretreatment with 10 microM 4-methylpyrazole, an inhibitor of alcohol dehydrogenase. Adenosine A1 and A2 receptors in primary cultures of rat hepatocytes are coupled to inhibition and stimulation of adenylyl cyclase, respectively. Since primary cultures of hepatocytes release adenosine into their extracellular media, we tested whether the acute effects of ethanol on cAMP were mediated by extracellular adenosine. Co-incubation with 2 U/mL adenosine deaminase prevented inhibition of cAMP production by 25-50 mM ethanol, but had no effect on stimulation by 100-200 mM ethanol. Pretreatment of hepatocytes with 110 nM 8-cyclopentyl-1,3-dimethylxanthine, an adenosine A1 receptor antagonist, also completely blocked the inhibitory effects of ethanol on cAMP production. Low concentrations of ethanol enhanced the inhibitory effects of R(-)N6-(2-phenylisopropyl)adenosine, an A1 receptor agonist, on cAMP production in cells pretreated with adenosine deaminase to remove endogenous adenosine. These data suggest that endogenously produced adenosine can be an important modulator of the effects of ethanol on receptor-stimulated cAMP production in primary cultures of rat hepatocytes.
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PMID:Role of adenosine A1 receptors in inhibition of receptor-stimulated cyclic AMP production by ethanol in hepatocytes. 780 99

Inhibition of forskolin-stimulated cAMP formation by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) in rat hippocampal slices was partially obliterated by the adenosine-depleting enzyme, adenosine deaminase, or by the adenosine receptor agonist, 5'-(N-ethylcarboxamido)-adenosine, suggesting that activation of metabotropic glutamate receptors (mGluRs) modulates the release of endogenous adenosine. Consistent with this hypothesis, forskolin stimulated the release of purines from rat hippocampal slices, and this effect was reduced by 1S,3R-ACPD. To establish which transduction pathway is involved in the modulation of forskolin-stimulated purine release, we have tested the novel mGluR2 agonist, (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), which reduced forskolin-stimulated cAMP formation but, as opposed to 1S,3R-ACPD, did not stimulate polyphosphoinositide hydrolysis. DCG-IV was highly potent and more efficacious than 1S,3R-ACPD in inhibiting forskolin-stimulated purine release. Neither DCG-IV nor 1S,3R-ACPD reduced the release of purines stimulated by depolarizing concentrations of K+, suggesting that their effect was stimulus-specific. These results indicate that, in rat hippocampal slices, activation of mGluR2 receptors attenuates the release of purines induced by forskolin, a process that amplifies the final effect of forskolin on cAMP formation as a result of A2 purinergic receptor activation. Thus, the final effect of mGluR agonists on forskolin-stimulated cAMP formation in hippocampal slices depends on both a direct inhibition of adenylyl cyclase and the inhibition of adenosine release.
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PMID:Interaction between metabotropic receptors and purinergic transmission in rat hippocampal slices. 806 75

The effects of theophylline upon human alveolar macrophage function were assessed and compared with its action upon macrophage cyclic nucleotide phosphodiesterase (PDE) activity and cyclic adenosine monophosphate (cAMP) levels. In the concentration range of 10 mumol/liter to 1 mmol/liter, theophylline caused a concentration-dependent inhibition of opsonized zymosan-stimulated hydrogen peroxide (H2O2) generation and PDE-catalyzed cAMP hydrolysis and increased the cellular cAMP content. Macrophage H2O2 generation was also inhibited by forskolin, an activator of adenylyl cyclase, but whereas theophylline (1 mmol/liter) and forskolin (1 mumol/liter) exhibited a synergic elevation of macrophage cAMP, there was no synergy between the two agents in the inhibition of respiratory burst. The inhibition of H2O2 generation by theophylline was reversed by the competitive inhibitor of cAMP-dependent protein kinase, (Rp)8-bromoadenosine cyclic 3':5'-monophosphorothioate (Rp-8-Br-cAMPS; 100 mumol/liter), indicating that the functional effect of theophylline was mediated through the elevation of cAMP. The inhibition of H2O2 generation by theophylline was not affected by adenosine deaminase (0.1 U/ml), indicating that the inhibition did not involve adenosine antagonism. It is concluded that theophylline exerts a direct inhibitory action upon human alveolar macrophage function through the elevation of cAMP levels as a result of PDE inhibition, and that this effect is observed at concentrations of theophylline that may be achieved in serum during therapy.
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PMID:Theophylline suppresses human alveolar macrophage respiratory burst through phosphodiesterase inhibition. 817 21

1. A newly found action of adenosine in neurons, which may have an important physiological function in the growth and development of the sympathetic nervous system, is described. Adenosine (1-100 microM) inhibited neurite outgrowth within the first 24 h and killed about 80% of sympathetic neurons supported by nerve growth factor over the next 2 days in culture. Neurons supported by excess KCl, forskolin or phorbol 12,13-dibutyrate were equally susceptible to the toxic actions of adenosine. Inosine, guanosine or hypoxanthine (all 100-300 microM) were without effect on neuronal growth and survival. 2. Specific agonists of adenosine A1 and A2 receptors were not neurotoxic, and toxic effects of adenosine were not antagonized by aminophylline. These results rule out involvement of adenosine receptors and the adenylyl cyclase-cAMP signalling system in neurotoxic actions of adenosine. 3. Adenosine toxicity was prevented by inhibitors of the adenosine membrane transporter, suggesting an intracellular site of action of adenosine. 4. Inhibitors of adenosine deaminase dramatically facilitated the toxic action so that physiologically relevant concentrations of adenosine were neurotoxic. 5. Adenosine kinase activity of sympathetic neurons was dose-dependently inhibited by 5'-iodotubercidin (3-100 nM). 5'-Iodotubercidin (100 nM) completely protected neurons against toxicity of adenosine plus adenosine deaminase inhibitors. These results provide convincing evidence that phosphorylation of the nucleoside is an essential requirement for initiation of adenosine toxicity. 6. Sympathetic neurons were successfully rescued from the lethal effects of adenosine deaminase inhibitor plus adenosine by uridine or 2-deoxycytidine, but not by nicotinamide or 2-deoxyguanosine, suggesting that depletion of pyrimidine nucleotides by phosphorylated adenosine compounds and consequent inhibition of DNA synthesis produces neuronal death. 7. DNA fragmentation, assessed by the fluorescent dye bisbenzimide and by the TUNEL (terminal deoxynucleotidyl transferase-mediated nick end labelling) method, indicated that neuronal death induced by adenosine was apoptotic. 8. We conclude that adenosine deaminase and adenosine kinase play an important role in the metabolism of intracellular concentrations of adenosine and thereby regulate the growth and development of sympathetic neurons. Our study highlights, for the first time, the importance of adenosine as a mediator of programmed cell death of neurons supported by nerve growth factor.
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PMID:Adenosine-induced apoptosis in chick embryonic sympathetic neurons: a new physiological role for adenosine. 856 48

The increase in human neutrophil cyclic adenosine monophosphate (cAMP) levels evoked by formylated peptides is significantly reduced in the presence of MDL 12330A, SQ 22536, GDPssS and clonidine, which inhibit the adenylyl cyclase system by acting at different sites in this enzyme complex. A similar effect is exerted by adenosine deaminase and dipyridamole, which alter the extracellular adenosine concentration. Neutrophil preincubation with adenylyl cyclase inhibitors or dipyridamole reduces chemotaxis and superoxide anion production triggered by peptides; adenosine deaminase, on the contrary, has no effect on neutrophil responses. Our results seem to indicate that: (1) the peptide-induced increase in neutrophil cAMP is due mainly to an action on the adenylyl cyclase system; (2) an enhancement of this cyclic nucleotide, even slight and necessarily transient, is required for chemotaxis and O2 production induced in neutrophils by formylated peptides; and (3) cAMP does not represent the crucial second messenger for adenosine in the modulation of neutrophil responses.
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PMID:Effect of cyclic AMP level reduction on human neutrophil responses to formylated peptides. 884 27

Hypothyroidism profoundly reduces the capacity of brown adipose tissue (BAT) to generate cAMP in response to adrenergic stimulation. Evidence obtained with isolated brown adipocytes suggests a postreceptor defect that offsets the hypothyroidism-induced increase in beta3-adrenergic receptors. The goal of the present studies was to identify the defect in the cAMP generation pathway for which we studied cAMP generation in isolated cells and purified BAT membranes from normal and hypothyroid rats. Studies with adenosine deaminase and the adenosine receptor-1 agonist r-phenyl isopropyl adenosine (R-PIA) show that hypothyroid cells are not more sensitive to adenosine (same EC50) but more inhibited by high concentrations of R-PIA. Pretreatment with pertussis toxin reduced the gap in cAMP generation between eu- and hypothyroid cells and the inhibition mediated by R-PIA, but did not normalize the cAMP response to forskolin in hypothyroid cells. Although purified euthyroid BAT membranes increased cAMP production with GTP concentrations up to submillimolar range, to plateau or slightly decrease at higher levels, hypothyroid membranes were weakly stimulated by low concentrations of GTP and markedly inhibited (>50%) at concentrations > or = 10(-4) M. When assayed at 0.3 mM ATP and 1 microM GTP, hypothyroid membranes actually generated more cAMP in response to forskolin, but this was reversed when GTP concentration was 1 mM. Immunoblotting studies showed no significant effects of hypothyroidism on the abundance of G(alpha)i or Gbeta subunits, and ADP ribosylation of G(alpha)i was only 45% increased in hypothyroidism in contrast to a 2.5-fold increase in hypothyroid white adipose tissue membranes from the same rats. Hypothyroid membranes also exhibited different kinetics regarding ATP, with higher cAMP generation at submillimolar concentrations but less at >1 mM ATP. Actually, at ATP concentrations >0.6 mM, cAMP generation was markedly inhibited in hypothyroid membranes. Fixing the concentration of free Mg++ in these experiments indicates that most of the inhibition seen in hypothyroid membranes is caused by ATP, whereas euthyroid membranes are more sensitive to changes in free Mg++. Ca++ +/- calmodulin did not stimulate adenylyl cyclase (AC) activity. On the contrary, AC activity was inhibited by Ca++ in a concentration-dependent manner, by as low as 100 nM free Ca++, and to greater extent in hypo- than in euthyroid membranes (maximal inhibition 60 vs. 25-30%). Our results suggest that, functionally, hypothyroidism causes a change in the AC of BAT membranes consistent with a relative or absolute increase in the type VI AC (AC-VI). The effects on this AC of nucleotides, Ca++, and Mg++ at concentrations prevailing in the hypothyroid brown adipocyte are probably the major factor in the reduced capacity of these cells to generate cAMP. These results also open the possibility of a novel, differential effect of thyroid hormone on AC expression, and support the concept that thyroid hormone affects the adrenergic signal transduction pathways in a tissue-selective manner.
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PMID:Effects of hypothyroidism on brown adipose tissue adenylyl cyclase activity. 894 Mar 79


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