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Published on: August 13, 2019
17 beta-estradiol activates rapid signaling pathways involved in rat pachytene spermatocytes apoptosis through GPR30
Adele Chimento1, Rosa Sirianni, Christelle Delalande
1Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende (CS), Italy.
Abstract:
Aim of the present study was to investigate whether estrogens were able to directly activate rapid signaling pathways controlling spermatogenesis in rat pachytene spermatocytes (PS). Classically, estrogens act by binding to estrogen receptors (ERs) alpha and beta. Recently, it has been demonstrated that rapid estrogen action can also be activated through the G-protein-coupled receptor (GPR)-30. Herein, we demonstrated that rat PS express ER alpha, ER beta and GPR30. Treatment of PS with estradiol (E2), the selective GPR30 agonist G1 and the selective ER alpha agonist PPT determined activation of ERK1/2 which are part of GPR30 signaling cascade. ERK1/2 activation in response to E2 and G1 was correlated to an increased phosphorylation of c-Jun. All treatments failed to induce these responses in the presence of EGFR inhibitor AG1478, ERK inhibitor PD98059 and ER inhibitor ICI182780. mRNA expression of cell cycle regulators cyclin A1 and B1 was downregulated by E2 and G1 while an up-regulation of proapoptotic factor Bax was observed in the same conditions. These data demonstrate that E2, working through both ER alpha and/or GPR30, activates in PS the rapid EGFR/ERK/c-Jun pathway, modulating the expression of genes involved in the balance between cellular proliferation and apoptosis.
Insights
Estrogens rapidly activate signaling pathways in rat sperm cells (pachytene spermatocytes) through estrogen receptors (ERs) and GPR30. This process influences genes controlling cell proliferation and apoptosis.
Area of Science:
- Reproductive Biology
- Molecular Endocrinology
- Cell Signaling
Background:
- Estrogens classically signal via estrogen receptors (ERs) alpha and beta.
- Rapid, non-classical estrogen signaling pathways are increasingly recognized.
- G-protein-coupled receptor 30 (GPR30) mediates some rapid estrogen actions.
Purpose of the Study:
- To investigate if estrogens directly activate rapid signaling pathways in rat pachytene spermatocytes (PS).
- To determine the role of ER alpha and GPR30 in mediating these rapid effects.
- To elucidate the downstream signaling cascade and gene expression changes involved.
Main Methods:
- Primary culture of rat pachytene spermatocytes (PS).
- Treatment with estradiol (E2), GPR30 agonist (G1), and ER alpha agonist (PPT).
- Assessment of ERK1/2 and c-Jun phosphorylation, gene expression (cyclin A1, B1, Bax), and pathway inhibition (EGFR, ERK, ER inhibitors).
Main Results:
- Rat PS express ER alpha, ER beta, and GPR30.
- E2, G1, and PPT activated the EGFR/ERK/c-Jun signaling cascade.
- These activations were dependent on EGFR, ERK, and ER signaling.
- E2 and G1 modulated mRNA expression of cell cycle regulators and proapoptotic factors.
Conclusions:
- Estrogens, via ER alpha and/or GPR30, activate rapid EGFR/ERK/c-Jun signaling in rat PS.
- This pathway influences the balance between proliferation and apoptosis during spermatogenesis.
- Identifies a novel rapid estrogen signaling mechanism in male germ cells.
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