Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate-specific membrane antigen (PSMA) is a 100 kDa type II transmembrane protein with folate hydrolase and NAALAdase activity. PSMA is highly expressed in prostate cancer and the vasculature of most solid tumors, and is currently the target of a number of diagnostic and therapeutic strategies. PSMA is also expressed in the brain, and is involved in conversion of the major neurotransmitter NAAG (N-acetyl-aspartyl glutamate) to NAA and free glutamate, the levels of which are disrupted in several neurological disorders including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease and schizophrenia. To facilitate analysis of the role of PSMA in carcinoma we have determined the structural organization of the gene. The gene consists of 19 exons spanning approximately 60 kb of genomic DNA. A 1244 nt portion of the 5' region of the PSMA gene was able to drive the firefly luciferase reporter gene in prostate but not breast-derived cell lines. We have mapped the gene encoding PSMA to 11p11-p12, however a gene homologous, but not identical, to PSMA exists on chromosome 11q14. Analysis of sequence differences between non-coding regions of the two genes suggests duplication and divergence occurred 22 million years ago.
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PMID:Mapping, genomic organization and promoter analysis of the human prostate-specific membrane antigen gene. 983 72

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

There is decreased activity of glutamate carboxypeptidase II (GCP II) in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of patients with schizophrenia. GCP II hydrolzses N-acetyl-alpha L-aspartyl-L-glutamate (NAAG), a peptide in the mammalian brain that binds to the N-methyl D-aspartate (NMDA) receptor and a group II metabotropic glutamate receptor, both of which have been implicated in the pathophysiology of schizophrenia. We examined the expression of GCP II mRNA in the DLPFC, entorhinal cortex (ERC), and hippocampus in postmortem samples from patients with schizophrenia and normal controls using in situ hybridization followed by silver grain detection. GCP II mRNA was detected in glial cells. Glial-rich regions, specifically the DLPFC and ERC white matter and the molecular and polymorphic layers in the hippocampus, express high levels of GCP II mRNA. Given the earlier finding of decreased GCP II activity in brains of subjects with schizophrenia, we expected to find lower GCP II mRNA levels in schizophrenia. Contrary to this expectation, we found a significantly higher expression of GCP II mRNA in one of the brain areas examined, the hippocampal CA3 polymorphic region. This may reflect a compensatory increase to correct for the decreased activity of GCP II activity. Our findings support the notion that the hydrolysis of NAAG is disrupted in schizophrenia and that specific anatomical regions may show discrete abnormalities in GCP II synthesis.
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PMID:Glutamate carboxypeptidase II gene expression in the human frontal and temporal lobe in schizophrenia. 1456 Mar 19

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

Glutamate carboxypeptidase II (GCPII) is a transmembrane glycoprotein expressed in various tissues. When expressed in the brain it cleaves the neurotransmitter N-acetylaspartylglutamate (NAAG), yielding free glutamate. In jejunum it hydrolyzes folylpoly-gamma-glutamate, thus facilitating folate absorption. The prostate form of GCPII, known as prostate specific membrane antigen (PSMA), is an established cancer marker. The NAAG-hydrolyzing activity of GCPII has been implicated in a number of pathological conditions in which glutamate is neurotoxic (e.g. amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, epilepsy, schizophrenia, and stroke). Inhibition of GCPII was shown to be neuroprotective in tissue culture and in animal models. GCPII is therefore an interesting putative therapeutic target. However, only very limited and controversial data on the expression and localization of GCPII in human brain are available. Therefore, we set out to analyze the activity and expression of GCPII in various compartments of the human brain using a radiolabeled substrate of the enzyme and the novel monoclonal antibody GCP-04, which recognizes an epitope on the extracellular portion of the enzyme and is more sensitive to GCPII than to the homologous GCPIII. We show that this antibody is more sensitive in immunoblots than the widely used antibody 7E11. By Western blot, we show that there are approximately 50-300 ng of GCPII/mg of total protein in human brain, depending on the specific area. Immunohistochemical analysis revealed that astrocytes specifically express GCPII in all parts of the brain. GCPII is enzymatically active and the level of activity follows the expression pattern. Using pure recombinant GCPII and homologous GCPIII, we conclude that GCPII is responsible for the majority of overall NAAG-hydrolyzing activity in the human brain.
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PMID:Expression of glutamate carboxypeptidase II in human brain. 1715 Mar 6

Experimental evidence is beginning to converge on an important role for dysregulation of glutamate carboxypeptidase II (GCPII) in schizophrenia. The goal of this study was to determine GCPII levels in postmortem brain specimens of patients with schizophrenia, bipolar disorder or unipolar depression and age-matched control subjects. We used N-[N-(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-[(125)I]iodo-l-tyrosine ([(125)I]DCIT), a high-affinity radioligand for GCPII, to probe for GCPII expression in prefrontal cortex (PFC) and mesial temporal lobe, two brain regions implicated in the pathophysiology of schizophrenia. We found that GCPII levels measured by [(125)I]DCIT quantitative autoradiography were significantly lower in the PFC and entorhinal cortex in patients with schizophrenia compared to age-matched controls. Patients with bipolar disorder also expressed significantly lower GCPII levels in PFC than controls. The decrease in [(125)I]DCIT binding in schizophrenia and bipolar disorder remained significant after adjusting for drug abuse. A significant difference in GCPII levels was also observed between schizophrenia relative to bipolar disorder and depressed subjects in the hippocampus-stratum lucidum and between schizophrenia and bipolar in the CA2 region of the hippocampus, with bipolar and depressed subjects expressing higher levels of GCPII than subjects with schizophrenia. These differences in hippocampal GCPII levels may implicate differences in the etiologies of these mental disorders. In summary, this study demonstrates a regional dysregulation of GCPII expression in the brain of patients with schizophrenia and other psychiatric disorders and supports a hypoglutamatergic state of the former illness. GCPII may represent a viable therapeutic target for intervention in psychiatric disease.
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PMID:Dysregulation of glutamate carboxypeptidase II in psychiatric disease. 1819 45

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

Glutamate carboxypeptidase II (GCP II) is a glial enzyme responsible for the hydrolysis of N-acetylaspartylglutamate (NAAG) into glutamate and N-acetylaspartate (NAA). Abnormalities in glutamate neurotransmission are implicated in the pathophysiology of schizophrenia. In this study, we examined the effects of a novel, orally active GCP II inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), on the prepulse inhibition (PPI) deficits after administration of the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine. Oral administration of 2-MPPA (10, 30 or 100mg/kg) significantly attenuated dizocilpine (0.1mg/kg)-induced PPI deficits in mice, in a dose dependent manner. Furthermore, the efficacy of 2-MPPA on dizocilpine-induced PPI deficits was significantly antagonized by pretreatment with the selective group II metabotropic glutamate receptor (mGluR) antagonist LY341495 (1.0mg/kg). In the same model, however, the selective group II mGluR agonist LY354740 (3, 10 or 30 mg/kg) significantly attenuated dizocilpine-induced PPI deficits at only one dose and prepulse intensity. Our findings suggest that GCP II inhibition may be useful therapeutic strategy for schizophrenia. From a mechanistic perspective, while increased NAAG and activation of group II mGluRs may contribute to the therapeutic efficacy of 2-MPPA, it is likely that additional pharmacological activities are also involved.
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PMID:Orally active glutamate carboxypeptidase II inhibitor 2-MPPA attenuates dizocilpine-induced prepulse inhibition deficits in mice. 2109 18

Interactions between genetic and environmental risk factors underlie a number of neuropsychiatric disorders, including schizophrenia (SZ) and autism (AD). Due to the complexity and multitude of the genetic and environmental factors attributed to these disorders, recent research strategies focus on elucidating the common molecular pathways through which these multiple risk factors may function. In this study, we examine the combined effects of a haplo-insufficiency of glutamate carboxypeptidase II (GCPII) and dietary folic acid deficiency. In addition to serving as a neuropeptidase, GCPII catalyzes the absorption of folate. GCPII and folate depletion interact within the one-carbon metabolic pathway and/or of modulate the glutamatergic system. Four groups of mice were tested: wild-type, GCPII hypomorphs, and wild-types and GCPII hypomorphs both fed a folate deficient diet. Due to sex differences in the prevalence of SZ and AD, both male and female mice were assessed on a number of behavioral tasks including locomotor activity, rotorod, social interaction, prepulse inhibition, and spatial memory. Wild-type mice of both sexes fed a folic acid deficient diet showed motor coordination impairments and cognitive deficits, while social interactions were decreased only in males. GCPII mutant mice of both sexes also exhibited reduced social propensities. In contrast, all folate-depleted GCPII hypomorphs performed similarly to untreated wild-type mice, suggesting that reduced GCPII expression and folate deficiency are mutually protective. Analyses of folate and neurometabolite levels associated with glutamatergic function suggest several potential mechanisms through which GCPII and folate may be interacting to create this protective effect.
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PMID:Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: implications for neurodevelopmental disorders. 2207 74


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