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 effects of a potent adenosine deaminase inhibitor, deoxycoformycin, on purine and amino acid neuro-transmitter release from the ischemic rat cerebral cortex were studied with the cortical cup technique. Cerebral ischemia (20 min) was elicited by four-vessel occlusion. Purine and amino acid releases were compared from control ischemic animals and deoxycoformycin-pretreated ischemic rats. Ischemia enhanced the release of glutamate, aspartate, and gamma-aminobutyric acid into cortical perfusates. The levels of adenosine, inosine, hypoxanthine, and xanthine in the same perfusates were also elevated during and following ischemia. Deoxycoformycin (500 micrograms/kg) enhanced ischemia-evoked release of adenosine, indicating a marked rise in the adenosine content of the interstitial fluid of the cerebral cortex. Inosine, hypoxanthine, and xanthine levels were depressed by deoxycoformycin. Deoxycoformycin pretreatment failed to alter the pattern of amino acid neurotransmitter release from the cerebral cortex in comparison with that observed in control ischemic animals. The failure of deoxycoformycin to attenuate amino acid neurotransmitter release, even though it markedly enhanced adenosine levels in the extracellular space, implies that the amino acid release during ischemia occurs via an adenosine-insensitive mechanism. Inhibition of excitotoxic amino acid release is unlikely to be responsible for the cerebroprotective actions of deoxycoformycin in the ischemic brain.
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PMID:Brain adenosine and transmitter amino acid release from the ischemic rat cerebral cortex: effects of the adenosine deaminase inhibitor deoxycoformycin. 167 Oct 90

Changes in adenosine 3',5'-cyclic monophosphate (cAMP) concentration were measured in cortical synaptosomes. Preincubation with adenosine deaminase reduced cAMP concentration by 45%. Oxotremorine, clonidine, gamma-aminobutyric acid (GABA) and baclofen produced no change in basal concentration. 2-Chloroadenosine and noradrenaline (NA), acting at beta-adrenoceptors, both caused a dose-dependent increase in cAMP; the NA-stimulated increase was depressed by GABA and by baclofen.
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PMID:The effect of presynaptic receptor stimulation on adenosine 3',5'-cyclic monophosphate concentrations in rat cortical synaptosomes. 300 40

1. Glutamate inhibits the electrically evoked release of noradrenaline in rabbit brain cortex slices; the inhibition is mediated by adenyl compounds, presumably adenosine. The aim of the present study was to identify the receptors involved in this indirect inhibitory effect of glutamate. Slices of the occipitoparietal cortex were preincubated with [3H]-noradrenaline and then superfused and stimulated by trains of 6 pulses, 100 Hz. 2. The ionotropic glutamate receptor agonists alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AM-PA; 10-100 microM), kainate (10-100 microM) and N-methyl-D-aspartate (NMDA; 30-300 microM) but not the metabotropic glutamate receptor agonist, 1-amino-1,3-cyclopentanedicarboxylate (ACPD; 10-100 microM) reduced the electrically evoked overflow of tritium. 3. The effects of AMPA, kainate and NMDA were attenuated or abolished by the adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) as well as by adenosine A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) as well as by adenosine deaminase but not by the alpha 2-adrenoceptor antagonist yohimbine, the gamma-aminobutyric acid (GABA) receptor antagonists, bicuculline and 2-hydroxysaclofen and the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). 4. The NMDA receptor antagonist, 2-amino-5-phosphonopentanoate (AP5) blocked the inhibitory effect of NMDA but not that of AMPA and kainate. The non-NMDA-receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocked the effect of AMPA but not of kainate and NMDA. 5. In addition to decreasing the electrically evoked overflow of tritium, AMPA, kainate and NMDA but not ACPD caused a steep but transient rise of basal tritium efflux. This immediate releasing effect was not significantly changed by DPCPX, adenosine deaminase, yohimbine, bicuculline, 2-hydroxysaclofen and L-NAME (except that L-NAME enhanced the effect of kainate). AP5 and CNQX antagonized the immediate releasing effects in the same way that they antagonized the inhibition by AMPA, kainate and NMDA of the electrically evoked overflow of tritium.6. It is concluded that AMPA, kainate and NMDA, like glutamate, reduce the electrically evoked release of noradrenaline by releasing adenosine or an adenine nucleotide which is then degraded to adenosine. Activation of each of the three ionotropic glutamate receptors, AMPA, kainate and NMDA receptors, but not activation of metabotropic glutamate receptors can initiate this indirect inhibitory effect on the release of noradrenaline (as well as the known noradrenaline releasing effect).
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PMID:Ionotropic glutamate receptor types leading to adenosine-mediated inhibition of electrically evoked [3H]-noradrenaline release in rabbit brain cortex slices. 750 27

Adenosine is a widespread neuromodulator that can be directly released in the extracellular space during sustained network activity or can be generated as the breakdown product of adenosine triphosphate (ATP). Whole cell patch-clamp recordings were performed from CA3 principal cells and interneurons in hippocampal slices obtained from P2-P7 neonatal rats to study the modulatory effects of adenosine on giant depolarizing potentials (GDPs) that constitute the hallmark of developmental networks. We found that GDPs were extremely sensitive to the inhibitory action of adenosine (IC(50) = 0.52 microM). Adenosine also contributed to the depressant effect of ATP as indicated by DPCPX-sensitive changes of ATP-induced reduction of GDP frequency. Similarly, adenosine exerted a strong inhibitory action on spontaneous glutamatergic synaptic events recorded from GABAergic interneurons and on interictal bursts that developed in CA3 principal cells after blockade of gamma-aminobutyric acid type A (GABA(A)) receptors with bicuculline. All these effects were prevented by DPCPX, indicating the involvement of inhibitory A1 receptors. In contrast, GABAergic synaptic events were not changed by adenosine. Consistent with the endogenous role of adenosine on network activity, DPCPX per se increased the frequency of GDPs, interictal bursts, and spontaneous glutamatergic synaptic events recorded from GABAergic interneurons. Moreover, the adenosine transport inhibitor NBTI and the adenosine deaminase blocker EHNA decreased the frequency of GDPs, thus providing further evidence that endogenous adenosine exerts a powerful control on GDP generation. We conclude that, in the neonatal rat hippocampus, the inhibitory action of adenosine on GDPs arises from the negative control of glutamatergic, but not GABAergic, inputs.
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PMID:Adenosine down-regulates giant depolarizing potentials in the developing rat hippocampus by exerting a negative control on glutamatergic inputs. 1609 35

Adenosine and gamma-aminobutyric acid (GABA) are both major inhibitory neuromodulators/neurotransmitters in the CNS. We now investigated if endogenous GABA modulates adenosine A(1)-mediated action on synaptic transmission in the hippocampus. Field excitatory postsynaptic potentials (fEPSP) were recorded from the CA(1) area of rat hippocampal slices. The adenosine analogue 2-chloroadenosine (0.15-1 microM) inhibited synaptic transmission with an EC(50) of 398 nM. Blocking GABA(A) receptors with the specific antagonists, bicuculline (10 microM) or picrotoxin (10 microM) potentiated the inhibitory effect of 2-chloroadenosine. The concentration-response curve for 2-chloroadenosine was displaced to the left by a factor of 2 (EC(50)=210 nM) in the presence of bicuculline (10 microM). GABA(A) receptor blockade also potentiated the action of N(6)-cyclopentyladenosine (CPA, 10 nM), a specific adenosine A(1) receptor agonist. Prevention of adenosine accumulation with adenosine deaminase (1 U/ml) did not influence bicuculline-induced potentiation of the effect of 2-chloroadenosine. The potentiation of adenosine A(1)-mediated response by bicuculline was abolished when nitric oxide (NO) synthase was inhibited with nitroarginine (100 microM), and when guanylyl cyclase was inhibited with 1H-[1,2,4]Oxadiazolo[4,3-a] quinoxalin-1-one (ODQ, 20 microM). The NO donors, (+/-)-S-nitroso-N-acetylpencillamine (SNAP, 300 microM) and diethylamine NONate diethylammonium salt (DEA/NO, 100 microM), significantly enhanced the inhibitory action of 2-chloroadenosine (150 nM). It is concluded that the blockade of GABA(A) receptors induces a potentiation of adenosine A(1) receptor-mediated inhibitory action, an effect that involves NO acting through guanylyl cyclase. Therefore, endogenous GABA might exert an inhibitory effect over adenosine A(1)-mediated responses in the hippocampus, which may represent a physiologic regulatory mechanism between the two inhibitory mediators.
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PMID:Nitric oxide mediates interactions between GABAA receptors and adenosine A1 receptors in the rat hippocampus. 1683 16

A-to-I pre-mRNA editing by adenosine deaminase enzymes has been reported to enhance protein diversity in the nervous system. In Drosophila, the resistance to dieldrin (RDL) gamma-aminobutyric acid (GABA) receptor subunit displays an editing site (R122) that is close to the putative GABA-binding site. We assessed the functional effects of editing at this site by expressing homomeric RDL receptors in Xenopus oocytes. After replacement of arginine 122 with a glycine, both agonist and fipronil potencies were shifted to the right in either fipronil-sensitive receptors or mutated resistant receptors (A301G/T350M). These data provide the first insight on the influence of RNA editing on GABA receptor function.
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PMID:RNA editing regulates insect gamma-aminobutyric acid receptor function and insecticide sensitivity. 1852 Sep 97

The lifespan of the predominant inhibitory neurotransmitter in the central nervous system, gamma-aminobutyric acid (GABA), is determined by its uptake into neurons and glia, through high-affinity Na(+)/Cl(-) dependent transporters (GATs). We now evaluated how the uptake of GABA by nerve endings, which is mostly mediated by the GAT-1 subtype, is modulated by brain-derived neurotrophic factor (BDNF). BDNF (10-200 ng/ml) decreased GAT-1-mediated GABA uptake by isolated hippocampal rat nerve terminals (synaptosomes), an effect that occurred within 1 min of incubation with BDNF and blocked by the tyrosine kinase inhibitor K252a (100 nM) as well as by the PLC inhibitor, U73122 (3 microM). Maximum inhibition was attained with 100 ng/ml BDNF. In contrast with what has been observed for other synaptic actions of BDNF, the inhibition of GABA transport by BDNF does not require tonic activation of adenosine A(2A) receptors since it was not blocked by the A(2A) receptor antagonist SCH 58261 (50 nM). However, in synaptosomes previously depleted of extracellular endogenous adenosine by incubation with adenosine deaminase (1 U/ml), activation of A(2A) receptors with the A(2A) receptor agonist, CGS 21680 (30 nM), enhanced the inhibitory effect of BDNF upon GABA transport, an action prevented by the A(2A) receptor antagonist, SCH 58261 (50 nM). It is concluded that BDNF, through TrkB and PLCgamma signalling inhibits GAT-1-mediated GABA transport by nerve endings and that this action is not dependent on, but can be enhanced by, TrkB/A(2A) receptor cross talk.
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PMID:Brain-derived neurotrophic factor inhibits GABA uptake by the rat hippocampal nerve terminals. 1853 66

We examined how the endogenous anticonvulsant adenosine might influence gamma-aminobutyric acid type A (GABA(A)) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 microM), GABA(A) receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABA(A)-current (I(GABA)) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/ml), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced I(GABA) run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated I(GABA) run-down in approximately 40% and approximately 20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 microM) potentiated I(GABA) run-down but only in approximately 20% of tested oocytes. CGS15943 administration again decreased I(GABA) run-down in patch-clamped neurons from either human or rat neocortex slices. I(GABA) run-down in pyramidal neurons was equivalent in A1 receptor-deficient and wt neurons but much larger in neurons from A2A receptor-deficient mice, indicating that, in mouse cortex, GABA(A)-receptor stability is tonically influenced by A2A but not by A1 receptors. I(GABA) run-down from wt mice was not affected by 2-CA, suggesting maximal ARs activity by endogenous adenosine. Our findings strongly suggest that cortical A2-A3 receptors alter the stability of GABA(A) receptors, which could offer therapeutic opportunities.
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PMID:Adenosine receptor antagonists alter the stability of human epileptic GABAA receptors. 1880 12

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