Membrane estrogen receptor (GPER) and follicle-stimulating hormone receptor heteromeric complexes promote human ovarian follicle survival
| Autor: | Francesca Fanelli, Francesco De Pascali, Manuela Simoni, Monica Lispi, Maria Teresa Villani, Silvia Limoncella, Aylin C. Hanyaloglu, Serena Marcozzi, Livio Casarini, Jessica Daolio, Clara Lazzaretti, Laura Riccetti, Elia Paradiso, Francesca Gioia Klinger, Angela Falbo, Giulia Brigante, Niamh S. Sayers, Francesco Potì, Claudia Anzivino, Giovanna Orlando, Jakub Czapinski, Eric Reiter, Adolfo Rivero-Müller, Beatrice Melli, Samantha Sperduti, Antonio La Marca |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Membrane estrogen receptor endocrine system Heteromer Biology Cell biology 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure Hormone receptor 030220 oncology & carcinogenesis medicine cAMP-dependent pathway Ovarian follicle Receptor Follicle-stimulating hormone receptor GPER 030304 developmental biology |
| DOI: | 10.1101/2020.04.21.053348 |
| Popis: | Classically, follicle stimulating hormone receptor (FSHR) driven cAMP-mediated signaling boosts human ovarian follicle growth and would be essential for oocyte maturation. However, contradicting in vitro suggest a different view on physiological and clinical significance of FSHR-mediated cAMP signaling. We found that the G protein coupled estrogen receptor (GPER) heteromerizes with FSHR, reprogramming cAMP/death signals into proliferative stimuli fundamental for sustaining oocyte survival. In human granulosa cells, survival signals are effectively delivered upon equal expression levels of both receptors, while they are missing at high FSHR:GPER ratio, which negatively impacts follicle maturation and strongly correlates with FSH responsiveness of patients undergoing controlled ovarian stimulation. Consistent with high FSHR expression levels during follicular selection, cell viability is dramatically reduced in FSHR overexpressing cells due to preferential coupling to the Gαs protein/cAMP pathway. In contrast, FSHR/GPER heteromer formation resulted in FSH-triggered anti-apoptotic/proliferative signaling delivered via the Gβγ dimer while heteromer impairment or GPER-associated Gαs inhibitory protein complexes resulted in cell death. GPER-depleted granulosa cells have an amplified FSH-dependent decrease in cell viability and steroidogenesis, consistent with the requirement of estrogen signaling for successful oocyte growth. Therefore, our findings indicate how oocyte maturation depends on the capability of GPER to shape FSHR selective signals, indicating hormone receptor heteromers may be a marker of cell proliferation.One Sentence SummaryFSHR/GPER heteromers block cAMP-dependent selection of ovarian follicles and target tumor growth and poor FSH-response in women. |
| Databáze: | OpenAIRE |
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