The novel estrogen receptor, G protein-coupled receptor 30, mediates the proliferative effects induced by 17β-estradiol on mouse spermatogonial GC-1 cell line

Rosa Sirianni, Adele Chimento, Carmen Ruggiero, Arianna De Luca, Rosamaria Lappano, Sebastiano Andò, Marcello Maggiolini, Vincenzo Pezzi

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127 Scopus citations

Abstract

Many studies have indicated that estrogens could have a role in the regulation of testicular function. However, it remains uncertain whether estrogens are able to directly activate signaling pathways in male germ cells. Estrogens are synthesized by the enzyme aromatase and classically act by binding to estrogen receptors (ERs)-α and ERβ. Knockout mice for both receptor isoforms exhibit a testicular phenotype that is less severe than aromatase knockout mice, suggesting the existence of an estrogen-binding receptor that may compensate for the lack of ERs. Recently studies using estrogen-sensitive tumor cell lines have demonstrated that the G-protein-coupled receptor (GPR)-30 binds and mediates estrogen action through the activation of the epidermal growth factor receptor (EGFR)/ERK/fos transduction pathway. The present study investigated the ability of 17β-estradiol (E2) to activate this pathway in the mouse spermatogonial cell line (GC-1). Using the GC-1 cell line as a model system, we demonstrated that GC-1 cells express GPR30 and ERα but not ERβ. E2, the selective GPR30 agonist G1, and the selective ERα agonist 4,4′,4″-(4-propyl-[1H]pyrazole-1,3,5- triyl) trisphenol activated the rapid ERK1/2-fos signaling cascade. This response was abrogated by the EGFR inhibitor AG1478, ERK inhibitor PD98059 and ER inhibitor ICI 182780, or by silencing GPR30 expression. Moreover, E2 and G1 up-regulated cyclin D1 expression and GC-1 cell proliferation. Our results indicate for the first time that estrogens, through a cross talk between GPR30 and ERα, activate the rapid EGFR/ERK/fos pathway, which in turn stimulate mouse GC-1 cell proliferation. Further studies to elucidate the involvement of rapid estrogen signaling pathways in the regulation of male fertility are warranted.

Original languageEnglish (US)
Pages (from-to)5043-5051
Number of pages9
JournalEndocrinology
Volume149
Issue number10
DOIs
StatePublished - Oct 1 2008

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ASJC Scopus subject areas

  • Endocrinology

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Sirianni, R., Chimento, A., Ruggiero, C., De Luca, A., Lappano, R., Andò, S., Maggiolini, M., & Pezzi, V. (2008). The novel estrogen receptor, G protein-coupled receptor 30, mediates the proliferative effects induced by 17β-estradiol on mouse spermatogonial GC-1 cell line. Endocrinology, 149(10), 5043-5051. https://doi.org/10.1210/en.2007-1593