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)

The D2-class of dopamine receptors (D2, D3, and D4) is a target for typical and atypical neuroleptic drugs. They have been considered, therefore, as factors that may contribute to the pathophysiology of psychotic disorders. Interestingly, in cortical brain tissues obtained postmortem form patients with chronic schizophrenia D3 mRNA was found to be significantly lower than in the corresponding anatomic regions of controls. Because the expression of a truncated D3-like mRNA (named D3nf) appeared to be unaffected in schizophrenic brains, these findings suggest the possibility that the loss of D3 mRNA results from an abnormal splicing of D3 pre-mRNA in schizophrenia that is accompanied by an increased accumulation of the truncated D3nf mRNA. To test this, three approaches were taken. (1) Substrate D3 pre-mRNA was spliced in vitro in HeLa nuclear extracts. Results from these experiments show that D3nf mRNA results from the alternative removal of a short spliceosomal intron in D3 pre-mRNA that has a noncanonical 3' splice site. (2) Substrate D3 pre-mRNA was spliced in vivo in stably transfected rat GH3 cells. Despite the atypical 3' cleavage that is necessary to generate D3nf mRNA, D3 and D3nf mRNA were found to be processed at similar amounts. (3) The relative D3/D3nf splicing efficiencies were then determined in the anterior cingulate cortex of postmortem brains obtained from controls and from patients with chronic schizophrenia. Significant differences were found between the relative levels of D3 and D3nf mRNA, suggesting that an enhanced D3nf-specific splicing of D3 pre-mRNA in schizophrenia leads to a decreased expression of D3 mRNA.
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PMID:Enhanced cleavage of an atypical intron of dopamine D3-receptor pre-mRNA in chronic schizophrenia. 898 18

We have generated a stable cell line expressing FLAG epitope-tagged D3 dopamine receptors and used this cell line to study D3 receptor-protein interactions. To analyze protein interactions, we separately introduced into the stable cell line either D3 receptors carrying an hemagglutinin (HA) epitope tag, or an HA-tagged version of the D3 receptor splice variant D3nf. A combination of confocal laser microscopy and coimmunoprecipitation was used to assay the formation and expression pattern of D3-D3 homodimers or D3-D3nf heterodimers. When coexpressed in HEK 293 cells, FLAG- and HA-tagged D3 receptors exhibited a similar plasma membrane distribution. Using an HA epitope tag-specific antibody, we coimmunoprecipitated HA- and FLAG-tagged D3 receptors, suggesting that D3 receptors are capable of forming homodimers. Epitope-tagged D3nf polypeptides exhibited a markedly different cellular distribution than D3 receptors. When expressed in HEK 293 cells, either alone or in combination with FLAG-tagged D3 receptors, D3nf exhibited a punctate perinuclear distribution. When D3nf was introduced into the stable D3-expressing cell line, D3 receptors were no longer visualized at the plasma membrane. Instead, D3 and D3nf showed a similar, predominantly cytosolic, localization. Using the HA-specific antibody, we were able to coimmunoprecipitate D3 and D3nf polypeptides from transfected cells. These data suggest the existence of physical interaction between D3 and D3nf. This interaction appears to result in the mislocalization of D3 receptors from the plasma membrane to an intracellular compartment, a finding that could be of significance in the etiology of schizophrenia.
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PMID:The dopamine D3 receptor interacts with itself and the truncated D3 splice variant d3nf: D3-D3nf interaction causes mislocalization of D3 receptors. 1099 36

Dopamine is a major neurotransmitter in the central nervous system, and its receptors are associated with a number of neuropathological disorders such as Parkinson's disease and schizophrenia. Although the precise pathophysiology of schizophrenia remains unknown, the dopaminergic hypothesis of the illness assumes that the illness results from excessive activity at dopamine synapses in the brain. Because, at present, the diagnosis of schizophrenia relies on descriptive behavioral and symptomatic information, a peripheral measurable marker may enable a simpler, more rapid, and more accurate diagnosis and monitoring. In recent years, human peripheral blood lymphocytes have been found to express several dopamine receptors (D(3), D(4), and D(5)) by using molecular biology techniques and binding assays. It has been suggested that these dopamine receptors found on lymphocytes may reflect receptors found in the brain. Here we demonstrate a correlation between the D(3) dopamine receptor on lymphocytes and schizophrenia and show a significant elevation of at least 2-fold in the mRNA level of the D(3), but not of the D(4), dopamine receptor in schizophrenic patients. This increase is not affected by different antipsychotic drug treatments (typical or atypical). Moreover, nonmedicated patients exhibit the same pattern, indicating that this change is not a result of medical treatment. We propose the D(3) receptor mRNA on blood lymphocytes as a marker for identification and followup of schizophrenia.
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PMID:A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes. 1114 51

The D(3) dopamine receptor has been implicated in several neuropsychiatric disorders, including schizophrenia, Parkinson's disease and addiction. Sequence variation in the D(3) gene can lead to subtle alteration in receptor structure or gene expression and thus to a different phenotype. In this study we examine the sequence variation in the D(3) gene in 96 rat strains and substrains. Interestingly, the analyses revealed 10 polymorphisms in the 5'flanking region and four polymorphisms in intronic regions of the gene. Moreover, two single nucleotide polymorphisms (SNPs) that result in amino acid changes were found in the last exon of the D(3) gene in the RNU/Mol strain. Additionally, bioinformatic analysis of the 5'flanking region and first intron of the gene revealed putative transcription factor binding sites that are conserved between mouse and human and are affected by the SNPs, possibly resulting in altered regulation of the subsequent transcription factor.
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PMID:Identifying polymorphisms in the Rattus norvegicus D3 dopamine receptor gene and regulatory region. 1514 9

D(3) dopamine receptor (D(3)R) is expressed mainly in parts of the brain that control the emotional behaviors. It is believed that the improper regulation of D(3)R is involved in the etiology of schizophrenia. Desensitization of D(3)R is weakly associated with G protein-coupled receptor kinase (GRK)/beta-arrestin-directed internalization. This suggests that there might be an alternative pathway that regulates D(3)R signaling. This report shows that D(3)R undergoes robust protein kinase C (PKC)-dependent sequestration that is accompanied by receptor phosphorylation and the desensitization of signaling. PKC-dependent D(3)R sequestration, which was enhanced by PKC-beta or -delta, was dynamin dependent but independent of GRK, beta-arrestin, or caveolin 1. Site-directed mutagenesis of all possible phosphorylation sites within the intracellular loops of D(3)R identified serine residues at positions 229 and 257 as the critical amino acids responsible for phorbol-12-myristate-13-acetate (PMA)-induced D(3)R phosphorylation, sequestration, and desensitization. In addition, the LxxY endocytosis motif, which is located between residues 252 and 255, was found to play accommodating roles for PMA-induced D(3)R sequestration. A continuous interaction with the actin-binding protein 280 (filamin A), which was previously known to interact with D(3)R, is required for PMA-induced D(3)R sequestration. In conclusion, the PKC-dependent but GRK-/beta-arrestin-independent phosphorylation of D(3)R is the main pathway responsible for the sequestration and desensitization of D(3)R. Filamin A is essential for both the efficient signaling and sequestration of D(3)R.
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PMID:Roles of protein kinase C and actin-binding protein 280 in the regulation of intracellular trafficking of dopamine D3 receptor. 1753 8

The analysis of data from matched pairs binary experiments, often performed with McNemar's test, presents a unique experimental design challenge in dealing with the effect of the discordance probability, p. Most approaches for determining size and power use point estimates or maximization, but this fails to account for the considerable variability across values of the nuisance parameter that occur for all common tests. We recommend viewing the size and power functions across the full range of possible discordance probability values, which gives a complete picture of the behavior of a test for any given sample size. This method also allows us to compare the behavior of different hypothesis tests. We present exact power and size functions for several tests, including the original McNemar's test and its most common variants, and compare their properties. This analysis reveals that, in general, McNemar's test comes closest to the nominal size and has the highest power. We also demonstrate our technique using the transmission/disequilibrium test (TDT) to check for linkage between schizophrenia and a locus related to the D(3) dopamine receptor, and on a hypnosis pain management data set.
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PMID:Efficient experimental design for binary matched pairs data. 1969 Oct 23