RESUMO
Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59=2.32, P=0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.
Assuntos
Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/psicologia , Córtex Pré-Frontal/metabolismo , Receptores de Glutamato/biossíntese , Receptores de N-Metil-D-Aspartato/metabolismo , Suicídio/psicologia , Adulto , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Expressão Gênica , Ácido Glutâmico/metabolismo , Humanos , Ketamina/uso terapêutico , Masculino , Receptores de Glutamato/genética , Fatores Sexuais , TranscriptomaRESUMO
The consumer electronics industry is a $240 billion global industry with a small number of highly competitive global players. We describe many of the risks associated with any global supply chain in this industry. As illustration, we also list steps that Samsung Electronics and its subsidiary, Samsung Electronics UK, have taken to mitigate these risks. Our description of the risks and illustration of mitigation efforts provides the backdrop to identify areas of future research.
RESUMO
5-HT(2C) receptor (5HT(2C)R, serotonin-2C) RNA undergoes editing to produce several receptor variants, some with pharmacological differences. This investigation comprised two parts: the characterisation of 5-HT(2C)R RNA editing in a larger human control sample than previously examined, and a comparative study in subjects with schizophrenia. Secondary structure analysis of the putative edited region of the human 5-HT(2C)R gene predicted the existence of a double stranded (ds) RNA loop, essential for RNA editing in this receptor. RNA was then extracted from frontal cortex of five controls and five subjects with schizophrenia. RT-PCR products of the edited region were cloned and sequenced (n = 100). Reduced RNA editing, increased expression of the unedited 5-HT(2C-INI) isoform in schizophrenia (P = 0.001) and decreased expression of the 5-HT(2C-VSV) and 5-HT(2C-VNV) isoforms were detected in the schizophrenia group. In addition, two novel mRNA edited variants were identified: 5-HT(2C-MNI) and 5-HT(2C-VDI). Screening of the 5-HT(2C)R gene did not reveal any mutations likely to disrupt the dsRNA loop, suggesting that the reduced RNA editing in schizophrenia may instead be caused by altered activity of the editing enzyme(s). Since the unedited 5-HT(2C-INI) is more efficiently coupled to G proteins than the other isoforms, its increased expression in schizophrenia may lead to enhanced 5-HT(2C)R-mediated effects. The results also illustrate that potentially important receptor alterations may occur in schizophrenia which are not detectable merely in terms of receptor abundance.
Assuntos
Córtex Cerebral/metabolismo , Conformação de Ácido Nucleico , Edição de RNA , RNA Mensageiro/química , RNA Mensageiro/genética , Receptores de Serotonina/genética , Esquizofrenia/genética , Animais , Sequência de Bases , Éxons , Variação Genética , Humanos , Íntrons , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/genética , Ratos , Receptor 5-HT2C de Serotonina , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A cysteine to serine substitution at amino acid 23 in the 5-HT2C receptor gene alters the pharmacological properties of the protein. We investigated this polymorphism in subjects with schizophrenia resistant to conventional neuroleptic drugs, and analysed our data for allelic association between the disease state or clinical response to the atypical antipsychotic drug, clozapine. Ninety percent of subjects who had one or more 5-HT2Cser alleles (19/21) were classified as clozapine responders compared with 59% (84/141) without this allele (chi 2 = 7.7, p = 0.005), suggesting that this mutation is a predictor of good response to clozapine. There was no association between schizophrenia and the 5-HT2Cser allele, but our results indicate that the 5-HT2C receptor may contain the major site of action through which clozapine mediates its antipsychotic effects.
