Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors.
The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17β-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics.
Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Christopher A
0000-0003-4949-3849
CA
Natale
Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Elizabeth K
0000-0003-1640-4205
EK
Duperret
Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Junqian
J
Zhang
Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Rochelle
R
Sadeghi
Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Ankit
A
Dahal
Department of Chemistry, University of Pennsylvania, Philadelphia, United States.
Kevin Tyler
0000-0002-9584-9589
KT
O'Brien
Department of Chemistry, University of Pennsylvania, Philadelphia, United States.
Rosa
R
Cookson
Department of Chemistry, University of Pennsylvania, Philadelphia, United States.
Jeffrey D
JD
Winkler
Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Todd W
0000-0001-8482-1284
TW
Ridky
D006801:Humans; D002478:Cells, Cultured; D004967:Estrogens / Q000378:metabolism; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012880:Skin Pigmentation
D004967:Estrogens; C109584:GPER1 protein, human; D008543:Melanins; D011374:Progesterone; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D011980:Receptors, Progesterone; C513556:PAQR7 protein, human
GPCR; cell biology; human; human biology; medicine; mouse; pigmentation; sex hormones