Transcriptional repression of the 5-HT1A receptor promoter by corticosterone via mineralocorticoid receptors depends on the cellular context

The diverse effects of the corticosteroid hormones are, mediated in large m easure by the mineralocorticoid and glucocorticoid receptors, two closely r elated members of the nuclear receptor superfamily. In the brain, corticost eroids regulate neuronal excitability and responses to neurotransmitters in a cell type-specific manner. The 5-HT1A receptor, for example, is highly e xpressed in the hippocampus and raphe but transcription is repressed by cor ticosterone (the principal glucocorticoid in rodents) only in hippocampus. We have used transient transfection of cultured cells to study the transcri ptional regulation of the 5-HT1A receptor promoter by activators and repres sion by glucocorticoids. We find that transcription factors Sp1 and NF-kapp a B subunit p65, both of which are coexpressed in hippocampus with the 5-HT 1A receptor in vivo, synergistically activate a reporter driven by receptor 5'-flanking region. Primer extension data suggest that the multiple transc ription initiation sites used in reporter gene transcription correlate with those used in transcription of the endogenous gene which has a TATA-less p romoter. Repression of transcription by corticosteroids was found to be med iated by both mineralocorticoid and glucocorticoid receptors, but not ident ically. 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-stimu lated reporter activity was not repressed via MR, whereas a similar level o f transcription resulting from synergistic activation by p65/Sp1-stimulatio n was repressed via MR. The context-dependence of these MR-mediated effects provides a model for the cell-type and state-dependent actions of corticos terone in the brain.