Commentary: harnessing the first peptidic modulator of the estrogen receptor GPER - Université Clermont Auvergne
Article Dans Une Revue Frontiers in Pharmacology Année : 2024

Commentary: harnessing the first peptidic modulator of the estrogen receptor GPER

Résumé

According to the pioneering work of Thomas et al., the G protein-coupled estrogen receptor GPER, a class A (rhodopsin-like) GPCR, interacts with estradiol (Thomas et al., 2005). This membrane protein is involved in a panel of pathophysiological actions including cardiovascular and digestive diseases (DeLeon et al., 2020; Groban et al., 2020), immune response (Notas et al., 2021), metabolic disorders (Sharma et al., 2018), neuroprotection (Pemberton et al., 2022) and cancer such as triple negative breast cancer (Zhang et al., 2024). Therefore, GPER has generated increasing attention in the scientific community and the synthesis of GPER modulators could open promising perspectives for the treatment of various diseases.

Recently, we have read with great interest the article published by E. Prossnitz and M. Barton entitled "The G protein-coupled estrogen receptor GPER in health and disease: an update" (Prossnitz and Barton, 2023). Although interesting, we consider that this article would benefit from our contribution to this fascinating field regarding the discovery of the first peptidic GPER modulator named ERα17p.

2 From the discovery to the anti-proliferative, antinociceptive and anti-inflammatory actions of ERα17p

The discovery of the peptide ERα17p and the assessment of its action through GPER is issued from European collaborations comprising research teams from Belgium, France, Greece and Italy. ERα17p corresponds to the residues 295-311 (hinge/AF2 region) and 123-139 of the human estrogen receptor α (ERα) and its isoform ERα36, respectively (primary sequence: PLMIKRSKKNSLALSLT).

In ERα-and GPER-positive ELT3 rat leiomyoma cells cultured under steroid-deprived conditions, ERα17p prompted proliferative activity through ERα, GPER, Gα i , EGFR, ERK1/ 2 and the translocation of β-arrestin. This effect being abolished by the GPER antagonist G-15 and a GPER siRNA, thus it occurred in a GPER-dependent manner (Leiber et al., 2015). In serum-cultured ERα-negative and GPER-positive MDA-MB-231 and SKBr3 human breast cancer cells, ERα17p was responsible for membrane-initiated molecular events leading to apoptosis in vitro and in vivo and, in the case of MDA-MB-231 cells, to the inhibition of migration (Kampa et al., 2011; Pelekanou et al., 2011). In similar conditions, ERα17p displayed anti-proliferative effects that were rescued by the selective GPER

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hal-04871148 , version 1 (07-01-2025)

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Rosamaria Lappano, Marcello Maggiolini, Christophe Mallet, Yves Jacquot. Commentary: harnessing the first peptidic modulator of the estrogen receptor GPER. Frontiers in Pharmacology, 2024, 15, pp.1413058. ⟨10.3389/fphar.2024.1413058⟩. ⟨hal-04871148⟩
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