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

Calcineurin (CaN), also designated as protein phosphatase 2B, is a major Ca2+/calmodulin-binding protein in the brain and the only serine/threonine phosphatase under the control of Ca2+/calmodulin. CaN activity has been implicated in downstream regulation of dopaminergic signal transduction and in NMDA receptor-dependent synaptic plasticity. Thus, it serves as a point of convergence for the abnormalities of these two neurotransmitter systems in schizophrenia. The aim of the present study was to determine if levels of CaN were altered in two schizophrenia- and CaN-related brain regions--the dorsolateral prefrontal cortex and hippocampus from subjects with schizophrenia compared to that in tissue from age and sex matched controls. CaN protein levels were measured by Western-blot analysis in samples from 15 schizophrenia patients vs. 15 control subjects. No significant differences in CaN protein levels were found either in the prefrontal cortex or in the hippocampus of schizophrenia patients compared to matched control subjects. Our result of lack of difference does not support the concept that brain CaN levels are a pathophysiological factor in this disorder. Further studies with antibodies against specific CaN catalytic subunit isoforms (presently unavailable) are required to resolve this issue.
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PMID:Postmortem brain calcineurin protein levels in schizophrenia patients are not different from controls. 1646 Sep 15

Association of the G72/G30 locus with schizophrenia and bipolar disorder has now been reported in several studies. The G72/G30 locus may be one of several that account for the evidence of linkage that spans a broad region of chromosome 13q. However, the story of G72/G30 is complex. Our meta-analysis of published association studies shows highly significant evidence of association between nucleotide variations in the G72/G30 region and schizophrenia, along with compelling evidence of association with bipolar disorder. But the associated alleles and haplotypes are not identical across studies, and some strongly associated variants are located approximately 50 kb telomeric of G72. Interestingly, G72 and G30 are transcribed in opposite directions; hence, their transcripts could cross-regulate translation. A functional native protein and functional motifs for G72 or G30 remain to be demonstrated. The interaction of G72 with d-amino acid oxidase, itself of interest as a modulator of N-methyl-d-aspartate receptors through regulation of d-serine levels, has been reported in one study and could be a key functional link that deserves further investigation. The association findings in the G72/G30 region, among the most compelling in psychiatry, may expose an important molecular pathway involved in susceptibility to schizophrenia and bipolar disorder.
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PMID:G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. 1658 Oct 30

NMDA receptor hypofunction (NRH) has been implicated in the pathophysiology of schizophrenia because of the ability of phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, to precipitate a schizophreniform psychosis. The possible role that NRH plays in the pathophysiology of schizophrenia stimulated characterization of behaviors elicited by PCP and its analogues. For example, MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist that binds with higher affinity to the same hydrophobic channel domain as PCP, raises the threshold voltage required for the electrical precipitation of tonic hindlimb extension in mice. This ability of MK-801 is significantly reduced following stress. We showed that an exogenously administered glycine prodrug (i.e., milacemide) was able to potentiate MK-801's antiseizure efficacy in unstressed mice and restore MK-801's antiseizure efficacy in stressed animals. d-Serine may serve as an endogenous agonist for the obligatory glycine co-agonist site on the NMDA receptor complex. Orally administered d-serine has been studied clinically as an adjuvant therapeutic intervention in schizophrenia. Thus, we were surprised at its inability to potentiate MK-801's antiseizure efficacy in either control or stressed animals. These data do not support the development of d-serine as a viable therapeutic intervention for schizophrenia and, possibly, other disorders.
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PMID:Exogenously administered D-serine failed to potentiate the ability of MK-801 to antagonize electrically precipitated seizures in nonhandled control and stressed mice. 1661 33

Prolyl oligopeptidase is a cytosolic serine peptidase that hydrolyzes proline-containing peptides at the carboxy termini of the proline residues. This peptidase has been associated with schizophrenia, bipolar affective disorder, and related neuropsychiatric disorders and might therefore have important clinical implications. Traditional Chinese medicinal (TCM) plants provide a rich source of unexplored compounds for strategies to find novel POP inhibitors, but the traditional methodologies used to identify POP inhibitors could have some limitations when working with natural products: interference with the colorimetric or fluorimetric detection methods commonly used to screen for POP inhibitors can result in the generation of false positives or false negatives. Since NMR screening is less prone to such interference, we decided to explore the use of 19F NMR to screen for POP inhibitors. We synthesized a new 19F-labeled POP substrate--Z-Gly-Pro-Phe-4(CF3)-NH2--and used it to search for new POP inhibitors in TCM plant extracts. We identified several plants with high POP-inhibitory activity and show here that the combination of 19F NMR and TCM plant extracts is a useful tool for identifying new POP inhibitors.
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PMID:Identification by 19F NMR of traditional Chinese medicinal plants possessing prolyl oligopeptidase inhibitory activity. 1662 53

Glycogen synthase kinase-3 (GSK3) has been recognized as an important enzyme that modulates many aspects of neuronal function. Accumulating evidence implicates abnormal activity of GSK3 in mood disorders and schizophrenia, and GSK3 is a potential protein kinase target for psychotropics used in these disorders. We previously reported that serotonin, a major neurotransmitter involved in mood disorders, regulates GSK3 by acutely increasing its N-terminal serine phosphorylation. The present study was undertaken to further determine if atypical antipsychotics, which have therapeutic effects in both mood disorders and schizophrenia, can regulate phospho-Ser-GSK3 and inhibit its activity. The results showed that acute treatment of mice with risperidone rapidly increased the level of brain phospho-Ser-GSK3 in the cortex, hippocampus, striatum, and cerebellum in a dose-dependent manner. Regulation of phospho-Ser-GSK3 was a shared effect among several atypical antipsychotics, including olanzapine, clozapine, quetiapine, and ziprasidone. In addition, combination treatment of mice with risperidone and a monoamine reuptake inhibitor antidepressant imipramine or fluoxetine elicited larger increases in brain phospho-Ser-GSK3 than each agent alone. Taken together, these results provide new information suggesting that atypical antipsychotics, in addition to mood stabilizers and antidepressants, can inhibit the activity of GSK3. These findings may support the pharmacological mechanisms of atypical antipsychotics in the treatment of mood disorders.
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PMID:Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics. 1678 49

Abnormalities of NMDA receptor-mediated neurotransmission are involved in the pathophysiology of schizophrenia, Alzheimer's disease, substance abuse and seizure disorders. The NMDA receptor is implicated in schizophrenia because phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, binds to a hydrophobic domain within the channel, precipitating a schizophreniform psychosis in susceptible persons. Pharmacological, environmental, and genetic variables alter NMDA receptor-mediated neurotransmission. Inbred mouse strains differ in their sensitivity to some of the behavioral effects of MK-801 (dizocilpine), a PCP analogue. The NMDA receptor complex in the BALB/c strain could reflect a unique stoichiometric combination of receptor subunits resulting in a higher proportion of the channels in the open configuration, a higher affinity of MK-801 for its hydrophobic channel domain, and/or a combination of the above. The BALB/c mouse strain, "stressed" mice, and behavioral consequences of MK-801 administration represent models of altered glutamatergic neural transmission. We were interested in examining the effect of stress on the modulatory properties of d-serine and sarcosine. d-Serine is a naturally occurring glycine agonist that modulates the ability of l-glutamate to influence the opening of the NMDA receptor-associated ionophore, and sarcosine is a naturally occurring glycine reuptake inhibitor. The data suggest that 24h after stress, d-serine and sarcosine interact synergistically to reduce MK-801's ability to antagonize electrically precipitated tonic hindlimb extension. Under conditions of stress, modulatory effects of d-serine and sarcosine on the antiseizure effect of MK-801 are observed that are not apparent in the nonstress condition. The results could be relevant to the development of glycinergic interventions for the treatment of neuropsychiatric disorders.
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PMID:Modulatory effects of d-serine and sarcosine on NMDA receptor-mediated neurotransmission are apparent after stress in the genetically inbred BALB/c mouse strain. 1671 29

Linkage studies in schizophrenia have identified a candidate region on chromosome 10p14-11 as reported for several independent samples. We investigated association of DNA sequence variants in a plausible candidate gene located in this region, the gene for phosphatidylinositol-4-phosphate 5-kinase IIalpha (PIP5K2A), in a sample of 65 sib-pair families for which linkage had been reported. Evidence for association was obtained for 15 polymorphisms spanning 73.6 kb in the genomic region of the gene between intron 4 and the 3' untranslated region, a region with high degree of linkage disequilibrium. Single nucleotide polymorphism (SNP) rs10828317 located in exon 7 and causing a non-synonymous amino-acid exchange (asparagine/serine) produced a P-value of 0.001 (experiment-wide significance level 0.00275) for over-transmission of the major allele coding for serine, analysed by transmission disequilibrium test using FAMHAP. Association of this SNP with schizophrenia has been also described in a sample of 273 Dutch schizophrenic patients and 580 controls (P=0.0004). PIP5K2A is involved in the biosynthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), one of the key metabolic crossroads in phosphoinositide signalling. PI(4,5)P2 plays a role in membrane transduction of neurotransmitter signals as well as in intracellular signalling, pathways that may be impaired in schizophrenia.
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PMID:Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia. 1680 50

Schizophrenia is a severe mental disorder, with worldwide prevalence of 1-1.5%. Immunological research in schizophrenia indicates that infectious or autoimmune processes might play a role in the etiopathogenesis. The complement system is a major mediator of innate immune defence against infection and contributes to many functions of the immune system including inflammation, opsonization and cell lysis. Mannan-binding lectin (MBL) activates the complement system via the lectin pathway. Inherited MBL deficiency, common in most human populations, predisposes to infectious and autoimmune diseases. We measured total complement activity (CH50), C4 activity (C4 CH50), MBL level and the activities of MBL-associated serine proteases, MASP-1 and MASP-2 in sera of 45 schizophrenic patients and in 62 healthy volunteers. We found that schizophrenic patients and healthy volunteers have statistically similar MBL levels and MASP-1 activity. However, MBL-bound MASP-2 activity and therefore MBL and MASP-2-mediated complement activation capacity is increased in schizophrenic patients compared with healthy volunteers (P<0.01). The increase was accompanied by increased CH50 (P<0.02) and C4 CH50 (P<0.02). Our results support the idea that complement system alterations may be involved in schizophrenia.
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PMID:Increased complement classical and mannan-binding lectin pathway activities in schizophrenia. 1686 Apr 75

The ability to selectively measure serine enantiomer concentrations in rat brain microdialysate is essential during drug discovery to study the interaction of d-serine with the N-methyl-d-aspartate (NMDA) subtype of the glutamate receptor. NMDA receptor-stimulating agents, such as d-serine, have been shown to reduce the negative symptoms and cognitive dysfunction in individuals with schizophrenia when added to conventional or atypical antipsychotic drug regimens. In the work presented here, an LC/MS/MS assay was developed and validated to simultaneously measure d-serine and l-serine concentrations in rat brain microdialysate. Reverse phase chromatographic resolution of the enantiomers was obtained through derivatization with 1-fluoro-2,4-dinitrophenyl-5-l-alanine amide (Marfey's reagent). The assay was validated to determine concentrations over the range of 10-7500 ng/mL using electrospray ionization and multiple reaction monitoring (MRM). Both intra- and inter-day precision and accuracy were less than 16.5% (RE) and 7% (CV) for both analytes, respectively, and assay throughput was increased significantly relative to existing methodologies.
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PMID:Quantification of serine enantiomers in rat brain microdialysate using Marfey's reagent and LC/MS/MS. 1696 91

Infections of unknown origin and an altered immune response have been hypothesized to play a role in the pathogenesis of schizophrenia. We have previously identified two single nucleotide polymorphisms (SNPs) of the IL-10 receptor 1 (IL-10R1) causing a substitution of glycine 330 to arginine (G330R) and of serine 138 to glycine (S138G). A possible association between these IL-10R1 variants and schizophrenia has been investigated in the present study. DNA of 101 unrelated Austrian patients with a DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders) consensus diagnosis of schizophrenia (n = 70) or schizoaffective disorder (n = 31) and DNA of 121 German schizophrenic patients (DSM-III-R) was analyzed for the presence of S138G and G330R by allele-specific multiplex PCRs. Data from patients were compared with 250 unrelated, psychiatric healthy controls. No difference in allele frequency was detected between patients and controls (G330R: 34.0% vs. 30.0%, P = 0.208; S138G: 19.7% vs. 16.6%, P = 0.235; by Fisher's exact test). However, there was a significant difference in genotype distribution (wt/wt, wt/mut, mut/mut) for G330R between patients (46.8%, 38.3%, 14.9%) and controls (47.6%, 44.8%, 7.6%; Fisher's test P = 0.032). No such difference was seen for S138G. Our results suggest that homozygosity of the IL-10R1 G330R allele is associated with schizophrenia and may contribute to the expression of disease phenotype in susceptible individuals.
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PMID:Homozygosity of the interleukin-10 receptor 1 G330R allele is associated with schizophrenia. 1706 77


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