Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The diverse effects of the corticosteroid hormones are mediated in large measure by the mineralocorticoid and glucocorticoid receptors, two closely related members of the nuclear receptor superfamily. In the brain, corticosteroids regulate neuronal excitability and responses to neurotransmitters in a cell type-specific manner. The 5-HT1A receptor, for example, is highly expressed in the hippocampus and raphe but transcription is repressed by corticosterone (the principal glucocorticoid in rodents) only in hippocampus. We have used transient transfection of cultured cells to study the transcriptional regulation of the 5-HT1A receptor promoter by activators and repression by glucocorticoids. We find that transcription factors Sp1 and NF-kB subunit p65, both of which are coexpressed in hippocampus with the 5-HT1A receptor in vivo, synergistically activate a reporter driven by receptor 5'-flanking region. Primer extension data suggest that the multiple transcription initiation sites used in reporter gene transcription correlate with those used in transcription of the endogenous gene which has a TATA-less promoter. Repression of transcription by corticosteroids was found to be mediated by both mineralocorticoid and glucocorticoid receptors, but not identically. While glucocorticoid receptors potently inhibited both p65- and p65/Sp1-stimulated transcription, repression via mineralocorticoid receptors (MR) depended on the transcriptional activators that were present: p65-stimulated reporter activity was not repressed via MR, whereas a similar level of transcription resulting from synergistic activation by p65/Sp1-stimulation was repressed via MR. The context-dependence of these MR-mediated effects provides a model for the cell-type and state-dependent actions of corticosterone in the brain.
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PMID:Transcriptional repression of the 5-HT1A receptor promoter by corticosterone via mineralocorticoid receptors depends on the cellular context. 1071 20

The serotonin 1A receptor (5-HT1A), a critical regulator of the brain serotonergic tone, is implicated in major depressive disorder (MDD) where it is often found to be dys-regulated. However, the extent to which stress and antidepressant treatment impact 5-HT1A expression in adults remains unclear. To address this issue, we subjected adult male BALB/c mice to unpredictable chronic mild stress (UCMS) to induce a depression-like phenotype that was reversed by chronic treatment with the antidepressant imipramine. In prefrontal cortex (PFC) and midbrain tissue, UCMS increased 5-HT1A RNA and protein levels, changes that are expected to decrease the brain serotonergic activity. The stress-induced increase in 5-HT1A expression was paralleled by a specific increase in DNA methylation of the conserved -681 CpG promoter site, located within a Sp1-like element. We show that the -681 CpG site is recognized and repressed by Sp4, the predominant neuronal Sp1-like factor and that Sp4-induced repression is attenuated by DNA methylation, despite a stress-induced increase in PFC Sp4 levels. These results indicate that adult life stress induces DNA methylation of a conserved promoter site, antagonizing Sp4 repression to increase 5-HT1A expression. Chronic imipramine treatment fully reversed the UCMS-induced increase in methylation of the -681 CpG site in the PFC but not midbrain of stressed animals and also increased 5-HT1A expression in the PFC of control animals. Incomplete reversal by imipramine of stress-induced changes in 5-HT1A methylation and expression indicates a persistence of stress vulnerability, and that sustained reversal of behavioral impairments may require additional pathways.
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PMID:Chronic mild stress and antidepressant treatment alter 5-HT1A receptor expression by modifying DNA methylation of a conserved Sp4 site. 2618 76