TY - JOUR
T1 - p21-Activated kinase mediates rapid estradiol-negative feedback actions in the reproductive axis
AU - Zhao, Zhen
AU - Park, Cheryl
AU - McDevitt, Melissa A.
AU - Glidewell-Kenney, Christine
AU - Chambon, Pierre
AU - Weiss, Jeffrey
AU - Jameson, J. Larry
AU - Levine, Jon E.
PY - 2009/4/28
Y1 - 2009/4/28
N2 - 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.
AB - 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.
KW - Estrogen receptor α
KW - GnRH
KW - LH
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U2 - 10.1073/pnas.0812597106
DO - 10.1073/pnas.0812597106
M3 - Article
C2 - 19359483
AN - SCOPUS:66349126271
SN - 0027-8424
VL - 106
SP - 7221
EP - 7226
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 17
ER -