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)

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

The pharmacology and cellular mechanism by which metabotropic glutamate receptor (mGluR) activation modulates cAMP formation was studied in cross-chopped hippocampal slices from neonatal (7 day old) rats. The selective mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), and other non-selective mGluR agonists produced concentration-related stimulation of basal cAMP formation in this tissue. The relative agonist potency order was 1S,3R-ACPD = quisqualate > ibotenate >> 1R,3S-ACPD. 1S,3R-ACPD stimulated cAMP accumulation was antagonized in a stereoselective manner by L-2-amino-3-phosphonopropionate (L-AP3), but not by higher chain homologues such as L-2-amino-4-phosphonobutyrate (L-AP4) and 2-amino-5-phosphonopentanoate (AP5). 1S,3R-ACPD-enhanced cAMP formation was greatly inhibited by incubation with adenosine deaminase. In the adult rat hippocampus, 1S,3R-ACPD did not appreciably increase basal cAMP, but inhibited forskolin-stimulated cAMP formation, and this effect was observed with or without adenosine deaminase. In the presence of the adenosine receptor antagonist and cAMP phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX), 1S,3R-ACPD did not enhance cAMP formation in the neonatal hippocampus, but inhibited forskolin-stimulated cAMP (like in the adult tissue). These results demonstrate that mGluRs that increase cAMP in the neonatal hippocampus have a unique pharmacology when compared to mGluRs that decrease cAMP accumulation and increase phosphoinositide hydrolysis. 1S,3R-ACPD stimulation of cAMP in the neonatal rat hippocampal slice involves potentiation of responses to endogenous adenosine. Negatively coupled cAMP linked mGluRs are also present in the neonatal tissue, but are masked by the predominance of the positively coupled mGluR cAMP response.
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PMID:Metabotropic glutamate receptor modulation of cAMP accumulation in the neonatal rat hippocampus. 751 34

KCl-evoked glutamate exocytosis from cerebrocortical synaptosomes can be inhibited by the adenosine A1 receptor agonist cyclohexyladenosine (CHA). Inhibition is associated with a decreased KCl-evoked Ca2+ level elevation, and the effect of the agonist is occluded by prior incubation with the Agelenopsis aperta neurotoxin omega-agatoxin-IVA at 250 nM. The inhibition is suppressed in the presence of 3 nM phorbol dibutyrate (PDBu) or by activation of the protein kinase C (PKC)-coupled metabotropic glutamate receptor by 100 microM (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)ACPD]. A tonic inhibition of release by leaked exogenous adenosine can be reversed by adenosine deaminase or by PDBu addition. The CHA-induced inhibition can be enhanced by the PKC inhibitor Ro 31-8220. The mechanism for the suppression of the adenosine A1 receptor-mediated inhibition is distinct from that previously described for the (1S,3R)ACPD-evoked, PKC-mediated, facilitatory pathway, which enhances phosphorylation of the MARCKS protein, 4-aminopyridine-induced action potentials, and release of glutamate because the latter requires at least 100 nM PDBu [or the combination of (1S,3R)ACPD and arachidonic acid] and is not seen following KCl depolarization. Both PKC-mediated pathways may be involved in the presynaptic events associated with the establishment of synaptic plasticity.
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PMID:Protein kinase C-mediated suppression of the presynaptic adenosine A1 receptor by a facilitatory metabotropic glutamate receptor. 761 16

The excitatory amino acid (EAA), L-cysteine sulfinic acid (L-CSA), elicited a dose-dependent increase in cAMP accumulation in adult rat hippocampus that was not blocked by ionotropic glutamate receptor antagonists. Therefore, the possibility was examined that L-CSA activates the (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD)-sensitive metabotropic glutamate receptor (mGluR) that increases cAMP by potentiating responses elicited by adenosine or other agonists of receptors coupled to adenylate cyclase via Gs. Like 1S,3R-ACPD, L-CSA induced a cAMP response that was inhibited by the adenosine receptor antagonist, 8-para-sulfyltheophylline, and by adenosine deaminase. In contrast to the 1S,3R-ACPD-induced cAMP response, the L-CSA-induced response was not potentiated by the adenosine uptake inhibitor, dipyridamole. Taken together with the previous finding that L-CSA does not potentiate cAMP responses elicited by agonists of receptors that activate Gs, these data suggest that L-CSA increases cAMP accumulation by activating a metabotropic EAA receptor that is different from the 1S,3R-ACPD-sensitive mGluR associated with potentiation of cAMP responses.
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PMID:An L-cysteine sulfinic acid-sensitive metabotropic receptor mediates increased cAMP accumulation in hippocampal slices. 773 95

Purified striatal synaptosomes were continuously superfused with L,3,5[3H]tyrosine in order to estimate the synthesis ([3H]water) and release of newly formed [3H]dopamine. In the presence of magnesium, L-glutamate, D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate (AMPA) and kainate, but not N-methyl-D-aspartate (NMDA) and 1-aminocyclopentane-1S,3R-dicarboxylate (t-ACPD), stimulated the release of [3H]dopamine, in a dose-dependent manner. When magnesium was omitted or in the presence of AMPA, NMDA also increased the release of [3H]dopamine. The effects of AMPA and kainate were competitively inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or 6,7-dinitro-quinoxaline-2,3-dione (DNQX), whereas those of NMDA were reduced by 2-amino-5-phosphonovalerate (APV) or (+)-5-methyl-10,11-dihydro-5-H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate (MK801). The stimulation of [3H]dopamine release by a high concentration of glutamate resulted from the concomitant activation of AMPA and NMDA receptors since this effect was potentiated by glycine and reduced by 2-amino-5-phosphonovalerate or MK801. This reduction was almost complete in the combined presence of DNQX and MK801. Surprisingly, glutamate and NMDA (in the absence of magnesium) reduced the efflux of [3H]water. The reduction of [3H]dopamine synthesis was blocked by 2-amino-5-phosphonovalerate indicating the involvement of NMDA receptors. Neither AMPA nor kainate affected dopamine synthesis. The inhibition of [3H]dopamine synthesis resulting from the stimulation of NMDA receptors was prevented when synaptosomes were continuously superfused with adenosine deaminase and quinpirole, a combined treatment known to markedly reduce the phosphorylation of tyrosine hydroxylase by cAMP-dependent protein kinase. The opposite effects of a high concentration of glutamate on [3H]dopamine synthesis and release were mimicked by ionomycin. As a working hypothesis, it is proposed that the NMDA-triggered calcium influx could lead to a reduction of tyrosine hydroxylase phosphorylation, possibly through an activation of calcineurin.
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PMID:Presynaptic control of dopamine synthesis and release by excitatory amino acids in rat striatal synaptosomes. 799 95

In rat cerebral cortical slices, the 1-aminocyclopentyl-1S,3R-dicarboxylate (1S,3R-ACPD) isomer of the selective metabotropic excitatory amino acid agonist ACPD inhibited forskolin-stimulated cyclic AMP (cAMP) accumulation in a concentration-dependent manner with a maximal inhibition of 51 +/- 3% and a half-maximally effective concentration of 8.8 +/- 3.4 microM. Similarly, 1R,3S-ACPD inhibited the forskolin response in a concentration-dependent manner, but with an inhibition of 80 +/- 5% at 3 mM. In addition to inhibiting forskolin-stimulated cAMP levels, 1S,3R-ACPD, but not 1R,3S-ACPD, enhanced the cAMP response to A2b adenosine receptor activation. In the presence of 1.2 U/ml of adenosine deaminase (included to reduce the contribution of endogenous adenosine), the efficacy of 1S,3R-ACPD was increased (88 +/- 3% inhibition), but the potency was unchanged. The adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine also increased the inhibitory effect of 100 microM 1S,3R-ACPD, from 57 +/- 1 to 78 +/- 5%. These results indicate that endogenous adenosine plays an important role in regulating the apparent efficacy of 1S,3R-ACPD inhibition of forskolin-stimulated cAMP accumulation in rat cerebral cortical slices and that previous studies in rat hippocampus and hypothalamus in the absence of added adenosine deaminase may have underestimated the efficacy of this compound.
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PMID:Endogenous adenosine regulates the apparent efficacy of 1-aminocyclopentyl-1S,3R-dicarboxylate inhibition of forskolin-stimulated cyclic AMP accumulation in rat cerebral cortical slices. 838 Apr 44

Metabotropic glutamate receptors (mGluRs) are coupled to effector systems through GTP-binding proteins (G-proteins) and appear to mediate slow synaptic responses in the CNS. Although mGluR-mediated increases in phosphoinositide hydrolysis have been well characterized, other mechanisms for signal transduction employed by mGluRs are poorly understood. We recently reported that the selective mGluR agonist 1-aminocyclopentane-1 S,3R-dicarboxylic acid (1S,3R-ACPD) increases cAMP accumulation in rat hippocampal slices. We have now investigated the mechanisms involved in this response. A number of G-protein-linked receptors that are not directly coupled to adenylate cyclase increase cAMP accumulation by potentiating cAMP responses to other agonists. Furthermore, previous studies suggest that glutamate increases cAMP accumulation by a mechanism that is dependent upon the presence of endogenous adenosine. Therefore, we tested the hypothesis that 1S,3R-ACPD-stimulated increases in cAMP accumulation in rat hippocampal slices are dependent upon the presence of endogenous adenosine and are mediated by an mGluR that potentiates cAMP responses to other agonists. We found that adenosine deaminase abolished 1S,3R-ACPD-stimulated cAMP accumulation whereas the adenosine uptake blocker dipyridamole enhanced this response. Additionally, adenosine receptor antagonists blocked mGluR-mediated increases in cAMP accumulation with potencies that were highly correlated with their potencies at A2 adenosine receptors. Furthermore, we performed a series of studies that suggest that 1S,3R-ACPD activates an mGluR subtype that potentiates responses to agonists of other receptors that are coupled to adenylate cyclase and that 1S,3R-ACPD-stimulated increases in cAMP accumulation in hippocampal slices are mediated by potentiation of the cAMP response to low levels of endogenous adenosine that are continuously present extracellularly.
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PMID:Activation of metabotropic glutamate receptors increases cAMP accumulation in hippocampus by potentiating responses to endogenous adenosine. 838 Aug 51

The effects of group 2- versus group 3-selective metabotropic glutamate (mGlu) receptor agonists were examined against forskolin (10 microM)-, vasoactive intestinal peptide (VIP; 1 microM)- and 5'-N-ethylcarboxamidoadenosine (NECA; 10 microM)-stimulated cAMP accumulations in adult rat hippocampal slices (in the presence of adenosine deaminase). Group 2 mGlu receptor-selective ((1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid (1S,3R-ACPD) and (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCG I)) and group 3 mGlu receptor-selective (L-2-amino-4-phosphonobutyric acid (L-AP4) and L-serine-O-phosphate) agonists greatly inhibited forskolin-stimulated cAMP formation ( > 80% at maximally effective concentrations). In contrast, stimulation of cAMP by VIP or NECA was inhibited by group 3, but not by group 2, mGlu receptor agonists. In fact, group 2 mGlu receptor agonists greatly potentiated cAMP accumulation evoked by NECA. Both the inhibitory effects of 1S,3R-ACPD on forskolin-stimulated cAMP and the potentiating effects on NECA-stimulated cAMP accumulation were reversed by the competitive group 1/2 mGlu receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG). However, (+)-MCPG had no effects on L-AP4 inhibition of cAMP. Thus, the effects of group 2 versus group 3 mGlu receptor agonists on cAMP coupling can be pharmacologically as well as functionally differentiated in the rat hippocampus.
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PMID:Differentiation of group 2 and group 3 metabotropic glutamate receptor cAMP responses in the rat hippocampus. 866 60

A pharmacological approach was used to investigate the cellular mechanism and metabotropic glutamate receptor (mGluR) subtypes that mediate stimulation of basal cyclic AMP (cAMP) formation in slices of the neonatal rat hippocampus. (1S,3 R)-1-Aminocyclopentane-1, 3-dicarboxylic acid (1S,3R-ACPD), which is an agonist for phosphoinositide-coupled and inhibitory-coupled cAMP-linked mGluRs in cloned and in situ preparations, produced prominent stimulations of basal cAMP levels (five- to 10-fold). However, the agonists 3,5-dihydroxyphenylglycine (DHPG) and (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), which selectively act on phosphoinositide-coupled and inhibitory cAMP-coupled mGluRs, respectively, only weakly increased cAMP levels. When these two mGluR subtype-selective agonists were added in combination, robust increases in cAMP levels, similar to those observed for 1S,3R-ACPD, were found. Stimulations of cAMP content evoked by 1S,3R-ACPD and combined additions of DHPG plus 2R,4R-APDC occurred at concentrations of these agents that directly couple to other mGluR second messenger responses. However, these stimulatory cAMP responses were prevented by the presence of adenosine deaminase and 8-p-sulfophenyltheophylline (an adenosine receptor antagonist), as well as (+)-alpha-methyl-4-carboxyphenylglycine (an mGluR receptor antagonist). Thus, 1S,3R-ACPD-induced increases in cAMP formation in the neonatal rat hippocampus are mediated by a synergistic interaction between mGluRs coupled to phosphoinositide (group 1) and inhibitory cAMP (group 2), which are indirectly expressed by potentiation of cAMP responses to other agonists (in this case, endogenous adenosine).
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PMID:(1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced increases in cyclic AMP formation in the neonatal rat hippocampus are mediated by a synergistic interaction between phosphoinositide- and inhibitory cyclic AMP-coupled mGluRs. 878 26

Guanine nucleotides (GN) have been implicated in many intracellular mechanisms. Extracellular actions, probably as glutamate receptor antagonists, have also been recently attributed to these compounds. GN may have a neuroprotective role by inhibiting excitotoxic events evoked by glutamate. Effects of extracellular GN on adenosine-evoked cellular responses have also been reported. However, the exact mechanism of such interaction is not known. In the present study, we showed that GN potentiated adenosine-induced cAMP accumulation in slices of hippocampus from young rats. However, neither GMP nor the metabotropic glutamate receptor agonist, 1S,3R-ACPD, inhibited the binding of the adenosine receptor agonist [3H]NECA (when binding to adenosine A2 receptors), or the binding of the adenosine A2a receptor agonist [3H]CGS 21680 in hippocampal membrane preparations. GppNHp, probably by interacting with G-proteins, decreased [3H]CGS 21680 binding. [3H]GMP binding was assayed in order to evaluate the GN sites which are not G-proteins. [3H]GMP binding was inhibited by GMP and GppNHp, but not by IS,3R-ACPD. The interaction of endogenous adenosine with the GMP-binding sites was determined by incubating membranes in the presence or absence of adenosine deaminase (ADA). NECA, CADO, CGS 21680 and CPA (only at the highest concentration used) increased GMP binding in the presence of ADA. However, in the absence of ADA, the control levels of GMP binding were as high as in the presence of added ADA plus adenosine agonists, indicating that endogenous adenosine modulates the binding of GMP. If this site has a neuroprotective role, adenosine may be increasing its neuromodulator and proposed protective action.
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PMID:Interaction of adenosine and guanine derivatives in the rat hippocampus: effects on cyclic AMP levels and on the binding of adenosine analogues and GMP. 1078


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