title: Activation of G protein-coupled estrogen receptor 1 mimics, but does not mediate, the anti-proliferative action of estradiol on pituitary lactotrophs in primary culture.
abstract: Estrogen binds to nuclear estrogen receptors (ERs) to modulate transcription of target genes in estrogen-responsive cells. However, recent studies have shown that estrogen also binds to cytoplasmic membrane ERs to modulate protein kinase signaling cascades, leading to non-genomic actions. We investigated whether either nuclear or membrane ERs, including G protein-coupled estrogen receptor 1 (Gper1), mediate the inhibitory action of estrogen on insulin-like growth factor-1 (IGF-1)-induced proliferation of pituitary lactotrophs in primary culture. The cytoplasmic membrane-impermeable bovine serum albumin-conjugated estradiol (BSA-E2) at 1 nM, an equimolar concentration at which 17β-estradiol (E2) exerts anti-proliferative effects, did not inhibit IGF-1-induced lactotroph proliferation. In contrast, diethylstilbestrol, which is known to selectively activate nuclear ERs but not membrane ERs, inhibited IGF-1-induced proliferation and modulated mRNA expression of estrogen-responsive genes to a similar degree as E2. Activation of Gper1 by its agonist G-1 inhibited IGF-1-induced proliferation in a dose-dependent manner, but it had little effect on modulation of mRNA expression of estrogen-responsive genes. However, blockade of Gper1 by its antagonist G-15 did not affect the inhibitory action of E2 on IGF-1-induced proliferation. Here, we demonstrate that E2 inhibition of lactotroph proliferation is due to nuclear ER-mediated genomic action. Our results suggest that activation of Gper1 mimics, but does not mediate, the anti-proliferative action of E2 on lactotrophs.
authors.affiliation: Department of Physiology, Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Mitsui
authors.forename: Maho
authors.initials: M
authors.lastname: Ishida
authors.forename: Michi
authors.initials: M
authors.lastname: Izawa
authors.forename: Jun
authors.initials: J
authors.lastname: Arita
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D052682:Lactotrophs / Q000187:drug effects* / Q000502:physiology; D061251:Primary Cell Culture; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C568862:4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline; D052117:Benzodioxoles; D004967:Estrogens; C520305:Gper1 protein, rat; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; C043090:estradiol-bovine serum albumin; D012710:Serum Albumin, Bovine; D004958:Estradiol; D007334:Insulin-Like Growth Factor I