Dataset Information

Abnormal glucocorticoid receptor mRNA and protein isoform expression in the prefrontal cortex in psychiatric illness.

ABSTRACT: Stress has been implicated in the onset and illness course of schizophrenia and bipolar disorder. The effects of stress in these disorders may be mediated by abnormalities of the hypothalamic-pituitary-adrenal axis, and its corticosteroid receptors. We investigated mRNA expression of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and protein expression of multiple GR? isoforms, in the prefrontal cortex of 37 schizophrenia cases and 37 matched controls. Quantitative real-time PCR, western blotting, and luciferase assays were employed. In multiple regression analysis, schizophrenia diagnosis was a significant predictor of total GR mRNA expression (p<0.05), which was decreased (11.4%) in schizophrenia cases relative to controls. No significant effect of diagnosis on MR mRNA was detected. At the protein level, no significant predictors of total GR? protein or the full-length GR? isoform were identified. However, schizophrenia diagnosis was a strong predictor (p<0.0005) of the abundance of a truncated ? 50 kDa GR? protein isoform, putative GR?-D1, which was increased in schizophrenia cases (80.4%) relative to controls. This finding was replicated in a second cohort of 35 schizophrenia cases, 34 bipolar disorder cases, and 35 controls, in which both schizophrenia and bipolar disorder diagnoses were significant predictors of putative GR?-D1 abundance (p<0.05 and p=0.005, respectively). Full-length GR? was increased in bipolar disorder relative to schizophrenia cases. Luciferase assays demonstrated that the GR?-D1 isoform can activate transcription at glucocorticoid response elements. These findings confirm total GR mRNA reductions in schizophrenia and provide the first evidence of GR protein isoform abnormalities in schizophrenia and bipolar disorder.

SUBMITTER: Sinclair D

PROVIDER: S-EPMC3230493 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Abnormal glucocorticoid receptor mRNA and protein isoform expression in the prefrontal cortex in psychiatric illness.

Sinclair Duncan D Tsai Shan Yuan SY Woon Heng Giap HG Weickert Cynthia Shannon CS

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20110831 13

Stress has been implicated in the onset and illness course of schizophrenia and bipolar disorder. The effects of stress in these disorders may be mediated by abnormalities of the hypothalamic-pituitary-adrenal axis, and its corticosteroid receptors. We investigated mRNA expression of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and protein expression of multiple GRα isoforms, in the prefrontal cortex of 37 schizophrenia cases and 37 matched controls. Quantitative real-ti ...[more]

PMID: 21881570

Similar Datasets

Project description:BackgroundWe previously identified a group of glucocorticoid-responsive genes, including Serum Glucocorticoid kinase 1 (Sgk1), regulated by acute ethanol in prefrontal cortex of DBA2/J mice. Acute ethanol activates the hypothalamic pituitary adrenal axis (HPA) causing release of glucocorticoids. Chronic ethanol dysregulates the HPA response in both humans and rodents, possibly contributing to important interactions between stress and alcoholism. Because Sgk1 regulates ion channels and learning and memory, we hypothesized that Sgk1 contributes to HPA-dependent acute and adaptive neuronal responses to ethanol. These studies characterized acute and chronic ethanol regulation of Sgk1 mRNA and protein and their relationship with ethanol actions on the HPA axis.ResultsAcute ethanol increased Sgk1 mRNA expression in a dose and time dependent manner. Three separate results suggested that ethanol regulated Sgk1 via circulating glucocorticoids: acute ethanol increased glucocorticoid receptor binding to the Sgk1 promoter; adrenalectomy blocked ethanol induction of Sgk1 mRNA; and chronic ethanol exposure during locomotor sensitization down-regulated HPA axis activation and Sgk1 induction by acute ethanol. SGK1 protein had complex temporal responses to acute ethanol with rapid and transient increases in Ser422 phosphorylation at 15 min. following ethanol administration. This activating phosphorylation had functional consequences, as suggested by increased phosphorylation of the known SGK1 target, N-myc downstream-regulated gene 1 (NDRG1). After repeated ethanol administration during locomotor sensitization, basal SGK1 protein phosphorylation increased despite blunting of Sgk1 mRNA induction by ethanol.ConclusionsThese results suggest that HPA axis and glucocorticoid receptor signaling mediate acute ethanol induction of Sgk1 transcription in mouse prefrontal cortex. However, acute ethanol also causes complex changes in SGK1 protein expression and activity. Chronic ethanol modifies both SGK1 protein and HPA-mediated induction of Sgk1 mRNA. These adaptive molecular responses of glucocorticoid-responsive gene expression and SGK1 in prefrontal cortex may contribute to mechanisms underlying behavioral responses to chronic ethanol exposure.

Dataset Information

Abnormal glucocorticoid receptor mRNA and protein isoform expression in the prefrontal cortex in psychiatric illness.

Publications

Abnormal glucocorticoid receptor mRNA and protein isoform expression in the prefrontal cortex in psychiatric illness.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets