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:3.4.17.21 (prostate-specific membrane antigen)
1,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-Acetylaspartylglutamate (NAAG) is a neuropeptide found in millimolar concentrations in brain that is localized to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neuronal systems. NAAG is released upon depolarization by a Ca(2+)-dependent process and is an agonist at mGluR3 receptors and an antagonist at NMDA receptors. NAAG is catabolized to N-acetylaspartate and glutamate primarily by glutamate carboxypeptidase II, which is expressed on the extracellular surface of astrocytes. The levels of NAAG and the activity of carboxypeptidase II are altered in a regionally specific fashion in several neuropsychiatric disorders.
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PMID:The nagging question of the function of N-acetylaspartylglutamate. 936 Dec 99

Glutamate carboxypeptidase II (GCPII, EC 3.14.17.21) is a membrane-bound enzyme found on the extracellular face ofglia. The gene for this enzyme is designated FOLH1 in humans and Folh1 in mice. This enzyme has been proposed to be responsible for inactivation of the neurotransmitter N-acetylaspartylglutamate (NAAG) following synaptic release. Mice harboring a disruption of the gene for GCPII/Folh1 were generated by inserting into the genome a targeting cassette in which the intron-exon boundary sequences of exons 1 and 2 were removed and stop codons were inserted in exons 1 and 2. Messenger RNA for GCPII was not detected by northern blotting or RT-PCR analysis of RNA from the brains of -/- mutant mice nor was GCPII protein detected on western blots of this tissue. These GCPII null mutant mice developed normally to adulthood and exhibited a normal range of neurologic responses and behaviors including mating, open field activity and retention of position in rotorod tests. No significant differences were observed among responses of wild type, heterozygous mutant and homozygous mutant mice on tail flick and hot plate latency tests. Glutamate, NAAG and mRNA for metabotropic glutamate receptor type 3 levels were not significantly altered in response to the deletion of glutamate carboxypeptidase II. A novel membrane-bound NAAG peptidase activity was discovered in brain, spinal cord and kidney of the GCPII knock out mice. The kinetic values for brain NAAG peptidase activity in the wild type and GCPII nullmutant were Vmax = 45 and 3 pmol/mg/min and Km = 2650 nm and 2494 nm, respectively. With the exception of magnesium and copper, this novel peptidase activity had a similar requirement for metal ions as GCPII. Two potent inhibitors of GCPII, 4,4'-phosphinicobis-(butane-1,3 dicarboxilic acid) (FN6) and 2-(phosphonomethyl)pentanedioic acid (2-PMPA) inhibited the residual activity. The IC50 value for 2-PMPA was about 1 nm for wild-type brain membrane NAAG peptidase activity consistent with its activity against cloned ratand human GCPII, and 88 nm for the activity in brain membranes of the null mutants.
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PMID:Deletion of the glutamate carboxypeptidase II gene in mice reveals a second enzyme activity that hydrolyzes N-acetylaspartylglutamate. 1235 25

Mounting evidence indicates that hypofunction of NMDA glutamate receptors causes or contributes to the full symptomatology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), an endogenous neuropeptide, blocks NMDA receptors and inhibits glutamate release by activating metabotropic mGluR3 receptors. NAAG is catabolized to glutamate and N-acetyl-aspartate by the astrocytic enzyme glutamate carboxypeptidase II (GCP II). Changes in GCP II activity may be critically linked to changes in glutamatergic neurotransmission especially at NMDA receptors. We examined whether GCP II function is altered by treatment with the noncompetitive antagonist and psychotomimetic drug phencyclidine (PCP) and with the neuroleptics haloperidol (HAL) and clozapine (CLOZ), in corticolimbic brain regions of the adult rat. Chronic exposure to PCP produced significant increases in GCP II protein expression and activity in the prefrontal cortex (PFC) and hippocampus (HIPP). This effect may be explained by a compensatory response to persistent blockade of NMDA receptors. In addition, chronic treatment with neuroleptics upregulated GCP II activity, but not protein expression, in the PFC. In contrast, GCP II activity was decreased after acute exposure to HAL or CLOZ and was not changed after acute PCP treatment. These findings provide support for a role of GCP II function in the control of glutamatergic neurotransmission and suggest that some of the therapeutic actions of neuroleptic drugs may be mediated through their effects on GCP II activity. These results demonstrate that psychotomimetic and neuroleptic drugs modulate GCP II function in brain regions that are widely involved in the neuropathology of schizophrenia.
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PMID:Regulation of glutamate carboxypeptidase II function in corticolimbic regions of rat brain by phencyclidine, haloperidol, and clozapine. 1270 Jul 5

Glutamate carboxypeptidase II (EC 3.4.17.21) catalyzes the hydrolysis (Km = 0.2 microM) of the neuropeptide N-acetylaspartylglutamate to yield N-acetylaspartate and glutamate and also serves as a high-affinity folate hydrolase in the gut, cleaving the polyglutamate chain to permit the absorption of folate. N-acetylaspartylglutamate is an agonist at the mGluR3 metabotropic receptor and a source of extracellular glutamate through hydrolysis by glutamate carboxypeptidase II. Given the important role of glutamate in brain development and function, we were interested in the effects of a null mutation of glutamate carboxypeptidase II that would potentiate the effects of N-acetylaspartylglutamate. The PGK-Neomycin cassette was inserted to delete exons 9 and 10, which we previously demonstrated encode for the zinc ligand domain essential for enzyme activity. Successful germline transmission was obtained from chimeras derived from embryonic stem cells with the targeted mutation of glutamate carboxypeptidase II. Homozygous null mutants did not survive beyond embryonic day 8. Folate supplementation of the heterozygous mothers did not rescue the homozygous embryos. Mice heterozygous for the null mutation appeared grossly normal and expressed both mutated and wild-type mRNA but the activity of glutamate carboxypeptidase II is comparable to the wild-type mice. The results indicate that the expression of glutamate carboxypeptidase II is upregulated when one allele is inactivated and that its activity is essential for early embryogenesis.
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PMID:Early embryonic death of glutamate carboxypeptidase II (NAALADase) homozygous mutants. 1455 33

N-Acetylaspartylglutamate (NAAG) is a peptide neurotransmitter present in the brain and spinal cord. It is hydrolysed by glutamate carboxypeptidase II (GCPII); thus, the GCP-II inhibitor 2-[phosphono-methyl]-pentanedioic acid (2-PMPA) protects endogenous NAAG from degradation, allowing its effects to be studied in vivo. We recorded the effect of spinal 2-PMPA (50-1000 microg) on the electrical-evoked activity of dorsal horn neurones in normal and carrageenan-inflamed animals, and in the spinal nerve ligation (SNL) model of neuropathy and sham-operated animals. In normal animals, 1000 microg 2-PMPA selectively inhibited noxious-evoked activity (input, post-discharge and C- and Adelta-fibre-evoked responses), and not low threshold Abeta-fibre-evoked responses. After carrageenan inflammation, the lower dose of 100 microg 2-PMPA inhibited input, post-discharge, C- and Adelta-fibre-evoked responses by a significantly greater amount than the same dose in normal animals. 2-PMPA inhibited neuronal responses less consistently in sham-operated and SNL animals, and effects were not significantly different from those seen in normal animals. NAAG is an agonist at the inhibitory metabotropic glutamate receptor mGluR3, and 2-PMPA may inhibit nociceptive transmission in normal animals by elevating synaptic NAAG levels, allowing it to activate mGluR3 and thus reducing transmitter release from afferent nerve terminals. mGluR3 expression in the superficial dorsal horn is upregulated after peripheral inflammation, perhaps explaining the greater inhibition of neuronal responses we observed after carrageenan inflammation. These results support an important role of endogenous NAAG in the spinal processing of noxious information.
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PMID:Effects of GCP-II inhibition on responses of dorsal horn neurones after inflammation and neuropathy: an electrophysiological study in the rat. 1460 7

Glutamate carboxypeptidase II (GCP II) inhibition has previously been shown to be protective against long-term neuropathy in diabetic animals. In the current study, we have determined that the GCP II inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) is protective against glucose-induced programmed cell death (PCD) and neurite degeneration in dorsal root ganglion (DRG) neurons in a cell culture model of diabetic neuropathy. In this model, inhibition of caspase activation is mediated through the group II metabotropic glutamate receptor, mGluR3. 2-PMPA neuroprotection is completely reversed by the mGluR3 antagonist (S)-alpha-ethylglutamic acid (EGLU). In contrast, group I and III mGluR inhibitors have no effect on 2-PMPA neuroprotection. Furthermore, we show that two mGluR3 agonists, the direct agonist (2R,4R)-4-aminopyrrolidine-2, 4-dicarboxylate (APDC) and N-acetyl-aspartyl-glutamate (NAAG) provide protection to neurons exposed to high glucose conditions, consistent with the concept that 2-PMPA neuroprotection is mediated by increased NAAG activity. Inhibition of GCP II or mGluR3 may represent a novel mechanism to treat neuronal degeneration under high-glucose conditions.
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PMID:Protection against glucose-induced neuronal death by NAAG and GCP II inhibition is regulated by mGluR3. 1503 Mar 92

Phencyclidine (PCP) administration elicits positive and negative symptoms that resemble those of schizophrenia and is widely accepted as a model for the study of this human disorder. Group II metabotropic glutamate receptor (mGluR) agonists have been reported to reduce the behavioral and neurochemical effects of PCP. The peptide neurotransmitter, N-acetylaspartylglutamate (NAAG), is a selective group II agonist. We synthesized and characterized a urea-based NAAG analogue, ZJ43. This novel compound is a potent inhibitor of enzymes, glutamate carboxypeptidase II (K(i) = 0.8 nM) and III (K(i) = 23 nM) that deactivate NAAG following synaptic release. ZJ43 (100 microM) does not directly interact with NMDA receptors or metabotropic glutamate receptors. Administration of ZJ43 significantly reduced PCP-induced motor activation, falling while walking, stereotypic circling behavior, and head movements. To test the hypothesis that this effect of ZJ43 was mediated by increasing the activation of mGluR3 via increased levels of extracellular NAAG, the group II mGluR selective antagonist LY341495 was co-administered with ZJ43 prior to PCP treatment. This antagonist completely reversed the effects of ZJ43. Additionally, LY341495 alone increased PCP-induced motor activity and head movements suggesting that normal levels of NAAG act to moderate the effect of PCP on motor activation via a group II mGluR. These data support the view that NAAG peptidase inhibitors may represent a new therapeutic approach to some of the components of schizophrenia that are modeled by PCP.
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PMID:NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. 1514 Jan 87

A group II metabotropic glutamate receptor (mGluR) agonist was recently reported to be clinically efficacious against symptoms of schizophrenia [Patil, S.T., Zhang, L., Martenyi, F., Lowe, S.L., Jackson, K.A., Andreev, B.V., Avedisova, A.S., Bardenstein, L.M., Gurovich, I.Y., Morozova, M.A., Mosolov, S.N., Neznanov, N.G., Reznik, A.M., Smulevich, A.B., Tochilov, V.A., Johnson, B.G., Monn, J.A., Schoepp, D.D., 2007. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nature Med 13, 1102-1107]. The endogenous neuropeptide N-acetylaspartylglutamate (NAAG) has been described as an agonist at mGluR2 and mGluR3 [Wroblewska, B., Wroblewski, J.T., Pshenichkin, S., Surin, A., Sullivan, S.E., Neale, J.H., 1997. N-acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J. Neurochem. 69, 174-181; Cartmell, J., Adam, G., Chaboz, S., Henningsen, R., Kemp, J.A., Klingelschmidt, A., Metzler, V., Monsma, F., Schaffhauser, H., Wichmann, J., Mutel, V., 1998. Characterization of [3H]-(2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl)glycine ([3H]-DCG IV) binding to metabotropic mGlu2 receptor-transfected cell membranes. Br. J. Pharmacol. 123, 497-504] and is degraded by the enzyme glutamate carboxypeptidase II (also known as N-acetyl-alpha-linked acidic dipeptidase or NAALADase). Hence, elevating the concentration of endogenous NAAG by inhibition of NAALADase represents a potential strategy for the treatment of schizophrenia via group II mGluR activation. We therefore investigated the activity of NAAG at both rat native and human recombinant mGluRs. We found that NAAG had no effect on synaptic transmission at the medial perforant pathway inputs to the rat dentate gyrus which is known to be sensitive to group II mGluR activation. We proceeded to examine the effects of NAAG at human recombinant mGluR2 and mGluR3 in a cellular G protein-activated K+ channel electrophysiology assay. Furthermore, due to discrepancies in the literature concerning the activity of NAAG at the N-methyl-d-aspartate receptor [NMDAR; Westbrook, G.L., Mayer, M.L., Namboodiri, M.A., Neale, J.H., 1986. High concentrations of N-acetylaspartylglutamate (NAAG) selectively activate NMDA receptors on mouse spinal cord neurons in cell culture. J. Neurosci. 6, 3385-3392; Losi, G., Vicini, S., Neale, J., 2004. NAAG fails to antagonize synaptic and extrasynaptic NMDA receptors in cerebellar granule neurons. Neuropharmacology 46, 490-496], we also tested NAAG at NMDARs in rat hippocampal neurons in culture. We found that a purified NAAG preparation had no effect at mGluR2, mGluR3 or NMDAR. Taken together, these findings do not support a rationale for targeting NAALADase and increasing extracellular NAAG levels as a therapeutic strategy for the treatment of schizophrenia.
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PMID:Effects of N-acetylaspartylglutamate (NAAG) at group II mGluRs and NMDAR. 1928 17

N-acetyl aspartyl glutamate (NAAG) is an endogenous agonist at the metabotropic glutamate receptor 3 (mGluR3,GRM3) receptor and antagonist at the N-methyl d-aspartate (NMDA) receptor, both receptors important to the pathophysiology of schizophrenia. Glutamate carboxypeptidase II (GCPII), an enzyme that metabolizes NAAG, is also implicated in this illness. In this study, we conducted in situ hybridization experiments to examine expression of mGluR3 and GCPII transcripts along the rostrocaudal axis of the human postmortem hippocampus. We hypothesized that we would find changes in mGluR3 and/or GCPII in the AH but not posterior hippocampus (PH) in schizophrenia. We compared mRNA levels of these genes in the dentate gyrus (DG) and cornu ammonis (CA)1 and CA3 of AH and PH in 20 matched pairs of control and schizophrenia cases. In controls, mGluR3 is highly expressed in the DG and at lower levels in CA1 and CA3 while GCP II is expressed at similar levels in these regions. Group comparisons show a significant reduction of GCPII mRNA level in the AH in schizophrenia. Post hoc analyses reveal this difference is localized to the CA1 region. In addition, we find a significant positive correlation between GCPII and mGluR3 mRNA in the CA3 of the control AH (r=0.66, p=0.008) which is not present in schizophrenia (r=0.096, p=0.76). This may reflect a disrupted functional interaction between NAAG and mGluR3 in CA3 in schizophrenia. These data suggest that NAAG-mediated signaling is disrupted in the AH in schizophrenia and localize the defect to the CA1 and CA3 regions.
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PMID:Localization of NAAG-related gene expression deficits to the anterior hippocampus in schizophrenia. 1940 71

The "glutamate" theory of schizophrenia emerged from the observation that phencyclidine (PCP), an open channel antagonist of the NMDA subtype of glutamate receptor, induces schizophrenia-like behaviors in humans. PCP also induces a complex set of behaviors in animal models of this disorder. PCP also increases glutamate and dopamine release in the medial prefrontal cortex and nucleus accumbens, brain regions associated with expression of psychosis. Increased motor activation is among the PCP-induced behaviors that have been widely validated as models for the characterization of new antipsychotic drugs. The peptide transmitter N-acetylaspartylglutamate (NAAG) activates a group II metabotropic receptor, mGluR3. Polymorphisms in this receptor have been associated with schizophrenia. Inhibitors of glutamate carboxypeptidase II, an enzyme that inactivates NAAG following synaptic release, reduce several behaviors induced by PCP in animal models. This research tested the hypothesis that two structurally distinct NAAG peptidase inhibitors, ZJ43 and 2-(phosphonomethyl)pentane-1,5-dioic acid, would elevate levels of synaptically released NAAG and reduce PCP-induced increases in glutamate and dopamine levels in the medial prefrontal cortex and nucleus accumbens. NAAG-like immunoreactivity was found in neurons and presumptive synaptic endings in both regions. These peptidase inhibitors reduced the motor activation effects of PCP while elevating extracellular NAAG levels. They also blocked PCP-induced increases in glutamate but not dopamine or its metabolites. The mGluR2/3 antagonist LY341495 blocked these behavioral and neurochemical effects of the peptidase inhibitors. The data reported here provide a foundation for assessment of the neurochemical mechanism through which NAAG achieves its antipsychotic-like behavioral effects and support the conclusion NAAG peptidase inhibitors warrant further study as a novel antipsychotic therapy aimed at mGluR3.
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PMID:Effects of N-acetylaspartylglutamate (NAAG) peptidase inhibition on release of glutamate and dopamine in prefrontal cortex and nucleus accumbens in phencyclidine model of schizophrenia. 2257 Apr 82


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