MC1R signaling. Intracellular partners and pathophysiological implications

Abstract

The melanocortin-1 receptor (MC1R) preferentially expressed in melanocytes is best known as a key regulator of the synthesis of epidermal melanin pigments. Its paracrine stimulation by keratinocyte-derived melanocortins also activates DNA repair pathways and antioxidant defenses to build a complex, multifaceted photoprotective response. Many MC1R actions rely on cAMP-dependent activation of two transcription factors, MITF and PGC1α, but pleiotropic MC1R signaling also involves activation of mitogen-activated kinases and AKT. MC1R partners such as β-arrestins, PTEN and the E3 ubiquitin ligase MGRN1 differentially regulate these pathways. The MC1R gene is complex and polymorphic, with frequent variants associated with skin phenotypes and increased cancer risk. We review current knowledge of signaling from canonical MC1R, its splice isoforms and natural polymorphic variants. Recently discovered intracellular targets and partners are also discussed, to highlight the diversity of mechanisms that may contribute to normal and pathological variation of pigmentation and sensitivity to solar radiation-induced damage. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.

Melanocortin-1 receptor (MC1R) genotypes do not correlate with size in two cohorts of medium-to-giant congenital melanocytic nevi

“…Children from dark-skinned populations of sub-Saharan Africa, in whom non-synonymous MC1R variants are rare (reviewed in Herraiz et al, 2017), also develop the largest, G2-type CMN (Katibi, Ogunbiyi, Brown & Adeyemi, 2014;Endomba, Mbega, Tochie & Petnga, 2018). Altogether, these data indicate that MC1R…”

Conjugation with Dihydrolipoic Acid Imparts Caffeic Acid Ester Potent Inhibitory Effect on Dopa Oxidase Activity of Human Tyrosinase

“…Mitf expression is normally activated via cAMP signaling following binding of α melanocyte-stimulating hormone (αMSH) to the melanocortin 1 receptor (MC1R), thus accounting for the induction of tyrosinase activity in melanocytes stimulated by αMSH [44,45]. Accordingly, it was of interest to determine whether in addition to the competitive inhibition of tyrosinase activity observed in the kinetic analysis described above, LCAME might also lead to reduced expression of tyrosinase in cells cultured in the presence of the compound.…”

SOX10 regulates multiple genes to direct eumelanin versus pheomelanin production in domestic rock pigeon

“…Our ultimate goal was to determine how downregulation of Sox10 in recessive red pigeons leads to the production of pheomelanin instead of eumelanin. Models suggest that modulation of Tyr expression is the primary factor regulating the switch between pigment types (Herraiz, Garcia‐Borron, Jiménez‐Cervantes, & Olivares, ). Somewhat surprisingly, neither the current data nor previous examinations identified any differences in Tyr expression between wild‐type and recessive red pigeons (Domyan et al, ).…”