EP936 - ECE_1975 - G-protein coupled estrogen receptor (GPER) modulates melanin prodution

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Abstract Melanin is produced by melanocytes to protect skin from UV radiation-mediated DNA damage. Melanogenesis is induced by α-melanocyte-stimulating hormone (α-MSH), which binds to melanocortin-1 receptor (MC1R) and requires the allosteric modulation by melanocortin receptor accessory protein (MRAP) to activate the cyclic adenosine monophosphate (cAMP) pathway. However, melanin excess occurs in pregnancy, during use of hormonal contraceptive pills, melanoma and melasma, suggesting that other hormones could be involved in melanogenesis. Our preliminary data demonstrated that skin hyperpigmentation may be due to overexpression of G protein-coupled estrogen receptor (GPER), another GPCR detected in skin cells and displaying MRAP-like allosteric behaviour. We aim to assess whether GPER may act as an allosteric partner for MC1R, leading to α-MSH-mediated melanin hyperproduction. Experiments were performed using skin tumour Sk-Mel-2 and Sk-Mel-28 cell lines, and human primary melanocytes over/under-expressing GPER. Cells were treated 48 h with 100 nM α-MSH, in the presence or in the absence of increasing doses (0-50 nM range) of estradiol and progesterone. MC1R, MRAP and GPER gene expression levels were evaluated by droplet-digital PCR, while the GPER-MC1R interaction by proximity ligation assay (PLA). Intracellular cAMP levels and melanin production were measured by bioluminescence resonance energy transfer (BRET) and spectrophotometric analysis. 5 independent experimental replicates were performed and statistically analysed by Kruskall-Wallis test and Dunn's post-test (P < 0.05). In transfected MC1R-expressing Sk-MEL-2 and -28 cell lines, α-MSH increases cAMP levels compared to untreated cells (P < .05), regardless of GPER and MRAP co-expression. Control experiments demonstrated that sex steroids failed to induce cAMP increase (P ≥ .05). Under GPER/MC1R and MRAP/MC1R co-expression, α-MSH leads to higher cAMP level increase than MC1R-expressing cells (P < .05). In primary melanocytes, nM progesterone concentrations induced GPER expression and melanin production in a steroid dose-dependent manner. Under progesterone exposure, melanocyte treatment with 100 nM α-MSH enhances the melanogenesis compared to progesterone-untreated cells (P < .05), while no effects were found under cell exposure to estradiol (P ≥ .05). Cell exposure to progesterone increases GPER expression, which replaces MRAP-specific allosteric functions and triggers marked response to α-MSH, as a mechanism leading to hyperpigmentation in melasma and skin cancer.

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