p21-Activated kinase mediates rapid estradiol-negative feedback actions in the reproductive axis

Zhen Zhao, Cheryl Park, Melissa A. McDevitt, Christine Glidewell-Kenney, Pierre Chambon, Jeffrey Weiss, J. Larry Jameson, Jon E. Levine

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Nonclassical estrogen receptor α (ERα) signaling can mediate E 2 negative feedback actions in the reproductive axis; however, downstream pathways conveying these effects remain unclear. These studies tested the hypothesis that p21-activated kinase 1 (PAK1), a serine/threonine kinase rapidly activated by E 2 in non-neural cells, functions as a downstream node for E 2 signaling pathways in cells of the preoptic area, and it may thereby mediate E 2 negative feedback effects. Treatment of ovariectomized (OVX) rats with estradiol benzoate (EB) caused rapid and transient induction of phosphorylated PAK1 immunoreactivity in the medial preoptic nucleus (MPN) but not the arcuate nucleus. To determine whether rapid induction of PAK phosphorylation by E 2 is mediated by nonclassical [estrogen response element (ERE)-independent] ERα signaling, we used female ERa null (ERα -/-) mice possessing an ER knock-in mutation (E207A/G208A; AA), in which the mutant ERa is incapable of binding DNA and can signal only through membrane-initiated or ERE-independent genotropic pathways (ERα -/AA mice). After 1-h EB treatment, the number of pPAK1-immunoreactive cells in the MPN was increased in both wild-type (ERα +/+) and ERα -/AA mice but was unchanged in ERα -/- mice. Serum luteinizing hormone (LH) was likewise suppressed within 1 h after EB treatment in ERα +/+ and ERα -/AA but not ERα -/- mice. In OVX rats, 5-min intracerebroventricular infusion of a PAK inhibitor peptide but not control peptide blocked rapid EB suppression of LH secretion. Taken together, our findings implicate PAK1 activation subsequent to nonclassical ERα signaling as an important component of the negative feedback actions of E 2 in the brain.

Original languageEnglish (US)
Pages (from-to)7221-7226
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Apr 28 2009


  • Estrogen receptor α
  • GnRH
  • LH

ASJC Scopus subject areas

  • General


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