GPR30 Does Not Mediate Estrogenic Responses in Reproductive Organs in Mice

Otto, Christiane; Fuchs, Iris; Kauselmann, Gunther; Heidrun, Kern; Zevnik, Branko; Andreasen, Puk; Schwarz, Gilda; Altmann, Helga; Klewer, Mario; Schoor, Michael; Vonk, Richardus; Fritzemeier, Karl-Heinrich

doi:10.1095/biolreprod.108.071175

Cited by 239 publications

(193 citation statements)

References 24 publications

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“…On balance, the current weight of evidence suggests that GPR30 is most likely a bona fide ER, and our data are similar to a recent report showing that GPR30 mRNA and protein are present in the term pregnant human myometrium (Maiti et al 2011). The role of GPR30 in reproduction and especially uterine function during pregnancy is unknown; however, GPR30 knockout mice have unimpaired fertility, retain normal uterine estrogenic responses, and appear to have normal pregnancies and parturition (Wang et al 2008, Isensee et al 2009, Otto et al 2009, Windahl et al 2009. Current data therefore suggest that the role of GPR30 in mediating estrogen actions in the pregnant myometrium is minimal.…”

Section: Discussionsupporting

confidence: 88%

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Welsh

Johnson

et al. 2011

Journal of Endocrinology

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Estrogens are thought to promote labor by increasing the expression of pro-contraction genes in myometrial cells. The specific estrogen receptors ((ERs: ERa and ERb (also known as ESR1 and ESR2)) and G protein-coupled receptor 30 (GPR30; also known as G protein-coupled estrogen receptor 1)) and signaling pathways that mediate these actions are not clearly understood. In this study, we identified the ERs expressed in the pregnant human myometrium and determined a key extranuclear signaling pathway through which estradiol (E 2 ) modulates expression of the gene encoding the oxytocin receptor (OXTR), a major pro-contraction protein. Using quantitative RT-PCR, we found that ERa and GPR30 mRNAs were expressed in the human pregnant myometrium while ERb mRNA was virtually undetectable. While mRNA encoding ERa was the predominant ER transcript in the pregnant myometrium, ERa protein was largely undetectable in myometrial tissue by immunoblotting. Pharmacological inhibition of 26S proteasome activity increased ERa protein abundance to detectable levels in term myometrial explants, however, indicating rapid turnover of ERa protein by proteasomal processing in the pregnant myometrium. E 2 stimulated rapid extranuclear signaling in myometrial explants, as evidenced by increased extracellularly regulated kinase (ERK1/2) phosphorylation within 10 min. This effect was inhibited by pre-treatment with an ER antagonist, ICI 182 780, indicating the involvement of ERa. Inhibition of ERK signaling abrogated the ability of E 2 to stimulate OXTR gene expression in myometrial explants. We conclude that estrogenic actions in the human myometrium during pregnancy, including the stimulation of contraction-associated gene expression, can be mediated by extranuclear signaling through ERa via activation of the ERK/mitogen-activated protein kinase pathway.

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Section: Discussionsupporting

confidence: 88%

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Welsh

Johnson

et al. 2011

Journal of Endocrinology

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“…E 2 can signal at the membrane to block cyst breakdown supporting the idea that a membrane receptor is involved (Chen et al 2009). Gpr30 knockout mice are fertile with no observable reproductive defects making it an unlikely candidate as the mER in neonatal ovaries (Otto et al 2009). …”

Section: Hormonesmentioning

confidence: 99%

Follicular assembly: mechanisms of action

Pepling¹

2012

Reproduction

211

190

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The differentiation of primordial germ cells (PGCs) into functional oocytes is important for the continuation of species. In mammals, PGCs begin to differentiate into oocytes during embryonic development. Oocytes develop in clusters called germ line cysts. During fetal or neonatal development, germ cell cysts break apart into single oocytes that become surrounded by pregranulosa cells to form primordial follicles. During the process of cyst breakdown, a subset of cells in each cyst undergoes cell death with only one-third of the initial number of oocytes surviving to form primordial follicles. The mechanisms that control cyst breakdown, oocyte survival, and follicle assembly are currently under investigation. This review describes the mechanisms that have been implicated in the control of primordial follicle formation, which include programmed cell death regulation, growth factor and other signaling pathways, regulation by transcription factors and hormones, meiotic progression, and changes in cell adhesion. Elucidation of mechanisms leading to formation of the primordial follicle pool will help research efforts in ovarian biology and improve treatments of female infertility, premature ovarian failure, and reproductive cancers.

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“…up to now, data on the expression of the GPR30 mRNa in tissues has not necessarily produced a consensus result, although various methods were used including northern blotting, RT-PcR methods, and RNase protection assays [9,10,[18][19][20][21] (Table 1). The mRNa for GPR30 appears to be expressed extensively in most tissues as judged from the overall reports.…”

Section: Expression Of Gpr30 Mrnamentioning

confidence: 99%

In Vivo Functions of GPR30/GPER-1, a Membrane Receptor for Estrogen: From Discovery to Functions In Vivo

Mizukami

2010

Endocr J

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Summary. G protein-coupled receptor 30/G protein-coupled estrogen receptor-1 (GPR30/GPER-1) was reported as a novel membrane receptor for estrogen in 2005. However, the research on GPR30 has produced conflicting reports with regard to its intracellular localization, the tissue distribution of its expression, and some its functions. Recently, in addition to the finding of G-1, a GPR30 agonist, GPR30 KO mice have been produced in laboratories, and this has significantly increased the confidence in the data. In this review, the intrinsic appearance of GPR30 is approached based mainly on data obtained in vivo.

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GPR30 Does Not Mediate Estrogenic Responses in Reproductive Organs in Mice

Cited by 239 publications

References 24 publications

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Follicular assembly: mechanisms of action

In Vivo Functions of GPR30/GPER-1, a Membrane Receptor for Estrogen: From Discovery to Functions In Vivo

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