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Molecular Endocrinology
Year: 2010  |  Volume: 24  |  Issue: 4  |  Page No.: 709 - 721

Involvement of Estrogen Receptor Variant ER-{alpha}36, Not GPR30, in Nongenomic Estrogen Signaling

L Kang, X Zhang, Y Xie, Y Tu, D Wang, Z Liu and Z. Y. Wang    

Abstract:

Accumulating evidence suggested that an orphan G protein-coupled receptor (GPR)30, mediates nongenomic responses to estrogen. The present study was performed to investigate the molecular mechanisms underlying GPR30 function. We found that knockdown of GPR30 expression in breast cancer SK-BR-3 cells down-regulated the expression levels of estrogen receptor (ER)-36, a variant of ER-. Introduction of a GPR30 expression vector into GPR30 nonexpressing cells induced endogenous ER-36 expression, and cotransfection assay demonstrated that GPR30 activated the promoter activity of ER-36 via an activator protein 1 binding site. Both 17β-estradiol (E2) and G1, a compound reported to be a selective GPR30 agonist, increased the phosphorylation levels of the MAPK/ERK1/2 in SK-BR-3 cells, which could be blocked by an anti-ER-36-specific antibody against its ligand-binding domain. G1 induced activities mediated by ER-36, such as transcription activation activity of a VP16-ER-36 fusion protein and activation of the MAPK/ERK1/2 in ER-36-expressing cells. ER-36-expressing cells, but not the nonexpressing cells, displayed high-affinity, specific E2 and G1 binding, and E2- and G1-induced intracellular Ca2+ mobilization only in ER-36 expressing cells. Taken together, our results demonstrated that previously reported activities of GPR30 in response to estrogen were through its ability to induce ER-36 expression. The selective G protein-coupled receptor (GPR)30 agonist G1 actually interacts with ER-36. Thus, the ER- variant ER-36, not GPR30, is involved in nongenomic estrogen signaling.

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