Estrogen regulation of the human 5-HT1A receptor gene

Abstract

Altered regulation of the 5-HT1A receptor is implicated in depression. Since depression is twice as prevalent in women versus men and major hormonal events in women trigger depression, I evaluated estrogen regulation of the 5-HT1A receptor in rat RN46A raphe cells. Estrogen (100 nM) induced no change in transcriptional activity of the 5-HT1A promoter (-1515bp/ATG). A putative estrogen response element (1AERE, -433bp) was identified in human and mouse but not rat 5-HT1A promoter. At least one nuclear protein complex from RN46A cells expressing estrogen receptor (ERbeta) bound specifically to the 1AERE, which mediated estrogen repression that was blocked upon mutational inactivation of 1AERE. Mutation of 1AERE derepressed the human 5-HT1A promoter but, paradoxically, estrogen induced rat 5-HT1A RNA in RN46A cells. Thus estrogen, via ERbeta action at 1AERE, represses human 5-HT1A promoter activity, but has an opposite effect on rat 5-HT1A expression that could reflect species-specific or post-transcriptional regulation.