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)

(-)-Stepholidine (SPD), an active ingredient of the Chinese herb Stephania, is the first compound found to have dual function as a dopamine receptor D1 agonist and D2 antagonist. Insights into dynamical behaviors of D1 and D2 receptors and their interaction modes with SPD are crucial in understanding the structural and functional characteristics of dopamine receptors. In this study a computational approach, integrating protein structure prediction, automated molecular docking, and molecular dynamics simulations were employed to investigate the dual action mechanism of SPD on the D1 and D2 receptors, with the eventual aim to develop new drugs for treating diseases affecting the central nervous system such as schizophrenia. The dynamics simulations revealed the surface features of the electrostatic potentials and the conformational "open-closed" process of the binding entrances of two dopamine receptors. Potential binding conformations of D1 and D2 receptors were obtained, and the D1-SPD and D2-SPD complexes were generated, which are in good agreement with most of experimental data. The D1-SPD structure shows that the K-167_EL-2-E-302_EL-3 (EL-2: extracellular loop 2; EL-3: extracellular loop 3) salt bridge plays an important role for both the conformational change of the extracellular domain and the binding of SPD. Based on our modeling and simulations, we proposed a mechanism of the dual action of SPD and a subsequent signal transduction model. Further mutagenesis and biophysical experiments are needed to test and improve our proposed dual action mechanism of SPD and signal transduction model.
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PMID:Dopamine D1 receptor agonist and D2 receptor antagonist effects of the natural product (-)-stepholidine: molecular modeling and dynamics simulations. 1746 75

Genetic factors have a variable impact on Alzheimer's Disease (AD), ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD, where a polygenic component is present. Most genes conferring susceptibility to AD are related to amyloid-beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha). Genome-wide analyses, transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability. Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes (COMT), transporters (5-HTTLPR) and receptors (DRD1; DRD3). Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia, while it is generally not recommended as a predictive testing for AD in asymptomatic individuals. Drugs currently in use to treat AD are effective in only 20% of patients; their therapeutic effect is predominantly under genetic control (CYP26 gene; APOE). Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression, schizophrenia and ADHD. The study of gene-environment interactions in AD, that are still poorly understood, is essential to predict disease-risk in asymptomatic individuals. Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti-AD drugs.
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PMID:Genetics of Alzheimer's disease. A rapidly evolving field. 1785 Nov 96

Although there is evidence to link schizophrenia (SCZ) and bipolar disorder (BD) to genetic and environmental factors, specific individual or groups of genes/factors causative of the disease have been elusive to the research community. An understanding of the molecular aberrations that cause these mental illnesses requires comprehensive approaches that examine both genetic and epigenetic factors. Because of the overwhelming evidence for the role of environmental factors in the disease presentation, our initial approach involved deciphering how epigenetic changes resulting from promoter DNA methylation affect gene expression in SCZ and BD. Apparently, the central reversible but covalent epigenetic modification to DNA is derived from methylation of the cytosine residues that is potentially heritable and can affect gene expression and downstream activities. Environmental factors can influence DNA methylation patterns and hence alter gene expression. Such changes can be especially problematic in individuals with genetic susceptibilities to specific diseases. Recent reports from our laboratory provided compelling evidence that both hyper- and hypo-DNA methylation changes of the regulatory regions play critical roles in defining the altered functionality of genes in major psychiatric disorders such as SCZ and BD. In this chapter, we outline the technical details of the methods that could help to expand this line of research to assist with compiling the differential methylation-mediated epigenetic alterations that are responsible for the pathogenesis of SCZ, BD, and other mental diseases. We use the genes of the extended dopaminergic (DAergic) system such as membrane-bound catechol-O-methyltransferase (MB-COMT), monoamine oxidase A (MAOA), dopamine transporter 1 (DAT1), tyrosine hydroxylase (TH), dopamine (DA) receptors1 and 2 (DRD1/2), and related genes (e.g., reelin [RELN] and brain-derived neurotrophic factor [BDNF]) to illustrate the associations between differential promoter DNA methylations and disease phenotype. It is our hope that comprehensive analyses of the DAergic system as the prototype could provide the impetus and molecular basis to uncover early markers for diagnosis, help in the understanding of differences in disease severity in individuals with similar or identical genetic makeup, and assist with the identification of novel targets for therapeutic applications.
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PMID:Epigenetic alterations of the dopaminergic system in major psychiatric disorders. 1837 Feb 35

In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.
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PMID:Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. 1858 79

Dopaminergic dysfunction in the prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. In the PFC, dopamine signalling largely depends on the D1 receptors, which are coded by the DRD1 gene, and on the regulation of dopamine levels by the enzyme catechol-O-methyltransferase (COMT). Here, we investigate the role of DRD1 and its interaction with the COMT gene in schizophrenic patients. In two gender-limited independent patient and control samples, we genotype five Tag single nucleotide polymorphisms (tagSNPs) of DRD1. The DRD1 SNP and haplotype associations, as well as interaction effects with the Val158Met COMT SNP were analyzed. In the male sample, we found the rs11746641 and rs11749676 DRD1 SNPs were associated with schizophrenia. Haplotype analyses identified the T-A-T-C-T variant related to a protective effect (P = 0.008) and the G-G-T-C-C variant that showed a tendency to be a risk factor for the disorder (P = 0.012). A logistic regression analysis revealed a significant pattern of interaction between DRD1 and COMT for both the rs11746641 (P = 0.002) and rs11749676 (P = 4.5 x 10(-5)) SNPs. DRD1-associated haplotypes were exclusively related to schizophrenia in the Val homozygous subgroup of patients (T-A-T-C-T: P = 0.003; G-G-T-C-C: P = 0.006). In females, none of the DRD1 SNPs were linked to the disorder. Our genetic data suggest that DRD1 and COMT are epistatically associated with protection against and the risk of developing schizophrenia in a gender-dependent fashion, and support the role of dopamine dysfunction at the PFC in the pathophysiology of this disorder.
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PMID:Sexually dimorphic interaction between the DRD1 and COMT genes in schizophrenia. 2012 86

Decreased dopaminergic activity in the prefrontal cortex (PFC) has been consistently reported in schizophrenia patients. The dopamine D1 receptor (DRD1) plays an important role in mediating dopaminergic transmission in the PFC. Controversy about this topic still exists despite ample evidence suggesting that the DRD1 gene is associated with performance on neuropsychological tests probing the function of the PFC in schizophrenia, as well as positive and negative symptoms and therapeutic response to antipsychotics. To determine whether this gene is involved in the etiology of schizophrenia, we undertook a case-control study to look for an association. We genotyped five single nucleotide polymorphisms (SNPs) rs4532, rs5326, rs2168631, rs6882300 and rs267418 within the DRD1 involving 373 schizophrenia patients with early age of onset and 379 healthy subjects. No significant differences of genotype, allele or haplotype distribution were identified between patients and controls. Our results do not preclude a possible role of DRD1 in the etiology of schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes. Further relevant studies are warranted.
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PMID:No genetic association between dopamine D1 receptor gene and [early onset] schizophrenia. 2038 33

Emerging evidence indicates that the DRD1-BDNF-DRD3 cluster plays an important role in nicotine addiction. We have performed an association analysis of 42 SNPs within these genes with cigarette consumption in a group of 341 schizophrenia patients. The ACCG haplotype consisting of four BDNF markers (Val66Met (rs6265), rs11030104, rs2049045 and rs7103411) showed an association with the risk of smoking (p = 0.0002). Both DRD1 markers tested (rs4532 and rs686) and the DRD3 marker (rs1025398) showed association with quantity of tobacco smoked (p = 0.01, 0.005 and 0.002, respectively). Our findings are preliminary; however, they support the involvement of the DRD1, BDNF and DRD3 genes in smoking behaviour.
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PMID:Association of polymorphisms in the BDNF, DRD1 and DRD3 genes with tobacco smoking in schizophrenia. 2045 19

The dysregulation of the dopaminergic system has been implicated in the pathophysiology of major psychosis, including schizophrenia, with dopamine receptor genes (DRDs) presently targeted as the most promising candidate genes. We investigated DRD1-5 for association with schizophrenia using a multi-stage approach in a Korean sample. One hundred forty-two SNPs in DRD1-5 were selected from the dbSNP, and the associations of each SNP were then screened and typed by MALDI-TOF mass spectrometry using pooled DNA samples from 150 patients with major psychosis and 150 controls. Each of the suggested SNPs was then genotyped and tested for an association within the individual samples comprising each pool. Finally, the positively associated SNPs were genotyped in an extended sample of 270 patients with schizophrenia and 350 controls. Among the 142 SNPs, 88 (62%) SNPs in our Korean population were polymorphic. At the pooling stage, 10 SNPs (DRD1: 2, DRD2: 3, and DRD4: 5) were identified (P<0.05). SNPs rs1799914 of DRD1 (P=0.046) and rs752306 of DRD4 (P=0.017) had significantly different allele frequencies in the individually genotyped samples comprising the pool. In the final stage, with the extended sample, the suggestive association of DRD4 with rs752306 was lost, but the association of DRD1 with rs1799914 gained greater significance (P=0.017). In these large-scale multi-stage analyses, we were able to find a possible association between DRD1 and schizophrenia. These findings suggested the potential contribution of a multi-step strategy for finding genes related to schizophrenia.
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PMID:Associations between DRDs and schizophrenia in a Korean population: multi-stage association analyses. 2117 90

Deficits in dopamine transmission at D1 receptors in the PFC are implicated in schizophrenia. Genetic polymorphisms in functional regions of DRD1 have a plausible role in modulating the risk of schizophrenia. In order to evaluate the role of DRD1 polymorphisms as a risk factor for schizophrenia, we performed a detailed analysis of possible functional single nucleotide polymorphisms (SNPs) in regulatory and coding regions of DRD1. Nine SNPs were identified by DNA sequencing in 20 patients with schizophrenia. Then 385 cases and 350 healthy control subjects were genotyped using the nine SNPs (rs4867798, rs686, rs1799914, rs4532 rs5326, rs265981, rs10078714, rs10063995, rs10078866). Statistically significant differences were observed in the allelic or genotypic frequencies of the rs686 and rs10063995 polymorphism in the DRD1 gene. A significantly lower risk of schizophrenia was associated with the G allele and AG+GG genotype of rs686 (OR (G allele)=0.632, 95%CI (G allele): 0.470-0.849; OR (AG+GG genotype)=0.578, 95%CI (AG+GG genotype): 0.416-0.803) compared with the A allele and AA genotype, respectively. And a significantly increased risk of schizophrenia was associated with the T allele of rs10063995 (OR=1.446, 95%CI: 1.125-1.859) compared with the G allele. The haplotype analysis indicated the G-T variant containing the T allele of rs10063995 is a risk for schizophrenia (P=0.005, OR=1.467, 95%CI: 1.123-1.917). These data suggest that DRD1 gene polymorphisms confer susceptibility to schizophrenia, and also support the notion that dysfunction of DRD1 is involved in the pathophysiological process of schizophrenia.
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PMID:An association study between dopamine D1 receptor gene polymorphisms and the risk of schizophrenia. 2195 27

In this study, we retrieved 39 schizophrenia-related antipsychotic drugs from the DrugBank database. These drugs had interactions with 142 targets, whose corresponding genes were defined as drug targeted genes. To explore the complexity between these drugs and their related genes in schizophrenia, we constructed a drug-target gene network. These genes were overrepresented in several pathways including: neuroactive ligand-receptor pathways, glutamate metabolism, and glycine metabolism. Through integrating the pathway information into a drug-gene network, we revealed a few bridge genes connected the sub-networks of the drug-gene network: GRIN2A, GRIN3B, GRIN2C, GRIN2B, DRD1, and DRD2. These genes encode ionotropic glutamate receptors belonging to the NMDA receptor family and dopamine receptors. Haloperidol was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug-gene interaction level during the treatment of schizophrenia. This study represents the first systematic investigation of drug-gene interactions in psychosis.
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PMID:Exploring schizophrenia drug-gene interactions through molecular network and pathway modeling. 2219 73


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