Estrogen receptor (ER)β isoforms rather than ERα regulate corticotropin-releasing hormone promoter activity through an alternate pathway

William J.Schouler Miller, Shotaro Suzuki, Lydia K. Miller, Robert Handa, Rosalie M. Uht

Research output: Contribution to journalArticle

78 Scopus citations


The hypothalamic-pituitary-adrenal axis regulates mammalian stress responses by secreting glucocorticoids. The magnitude of the response is in part determined by gender, for in response to a given Stressor, circulating glucocorticoids reach higher levels in female rats than in males. This gender difference could result from estrogen regulation of the corticotropin-releasing hormone (CRH) promoter via either of its receptors: estrogen receptor (ER) α or ERβ. Immunocytochemistry revealed that a subset (12%) of medial parvocellular CRH neurons in the rat hypothalamus contain ERβ but not ERα. To determine whether ERs could regulate CRH promoter activity, we cotransfected cells with a CRH promoter construct and either ERα or individual ERβ isoforms. ERα weakly stimulated CRH promoter transcriptional activity in a ligand-independent manner. Conversely, all ERβ isoforms tested stimulated CRH promoter activity with different ligand profiles. ERβ1 and ERβ2δ3 displayed constitutive activity (ERβ1 more than ERβ2δ3). Ligand-dependent activity of β isoforms 1 and 2 was altered by an Exon3 splice variant (δ3) or by the additional 18 amino acids in the ligand-binding domain of ERβ2 isoforms. Lastly, we suggest that ER regulation of CRH takes place through an alternate pathway, one that requires protein-protein interactions with other transcription factors or their associated complexes. However, a pure ER-activator protein-1 alternate pathway does not appear to be involved.

Original languageEnglish (US)
Pages (from-to)10628-10635
Number of pages8
JournalJournal of Neuroscience
Issue number47
StatePublished - Nov 24 2004
Externally publishedYes



  • Corticotropin-releasing hormone
  • Estradiol
  • Estrogen receptor α
  • Estrogen receptor β
  • Stress
  • Tamoxifen

ASJC Scopus subject areas

  • Neuroscience(all)

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