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 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

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

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

Signal transduction mechanisms of group II metabotropic glutamate receptors (mGlu(2/3)) remains a matter of some controversy, therefore we sought to gain new insights into its regulation by studying cAMP production in cultured neurons and astrocytes, and by examining inter-relationships of mGlu(2/3)-induced signalling with cellular calcium and various signalling cascades. mGlu(2/3) agonists 2R,4R-4-aminopyrrolidine-2,4-dicarboxylic acid (2R,4R-APDC) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) inhibited 10 microM forskolin-stimulated production of cAMP in murine cortical neurons, striatal neurons and forebrain astrocytes in the absence of extracellular Ca(2+). These agonists potentiated cAMP production in the presence of 1.8 mM Ca(2+) in astrocytes only. This potentiation was dependent on the extracellular Ca(2+) concentration (0.001-10 mM) and inhibited by the mGlu(2/3) antagonist LY341495 (1 microM), adenosine deaminase (1 U/ml) and the adenosine A(2A) receptor antagonist ZM241385 (1 microM). Pre-incubation with the phospholipase C (PLC) inhibitor U73122 (10 microM), L-type Ca(2+)-channel blockers nifedipine (1 microM) and nimodipine (1 microM), the calmodulin kinase II (CaMKII) inhibitor KN-62 (10 microM) or pertussis toxin (100 ng/ml) inhibited this potentiation. In the absence of 1.8 mM Ca(2+), thapsigargin (1 microM) facilitated the potentiation of cAMP production. Measurement of the Ca(2+)-binding dye Fluo-3/AM showed that, compared to Ca(2+)-free conditions, thapsigargin and 1.8 mM Ca(2+) elevated [Ca(2+)](i) in astrocytes; the latter effect being prevented by L-type Ca(2+)-channel blockers. Potentiation of cAMP production was also demonstrated when astrocytes were stimulated with the beta-adrenoceptor agonist isoprenaline (10 microM) in the presence of 1.8 mM Ca(2+), but not with the adenosine agonist NECA (10 microM) or the group I mGlu receptor agonist DHPG (100 microM). BaCl(2) (1.8 mM) in place of Ca(2+) did not facilitate forskolin-stimulated mGlu(2/3)-potentiation of cAMP. In short, this study in astrocytes demonstrates that under physiological Ca(2+) and adenylate cyclase stimulation an elevation of cAMP production is achieved that is mediated by PLC/IP(3)- and CaMKII-dependent pathways and results in the release of endogenous adenosine which acts at G(s) protein-coupled A(2A) receptors. These findings provide new insights into mGlu(2/3) signalling in astrocytes versus neurons, and which could determine the functional phenotypy of astrocytes under physiological and pathological conditions.
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PMID:Astrocyte mGlu(2/3)-mediated cAMP potentiation is calcium sensitive: studies in murine neuronal and astrocyte cultures. 1221 73