An overview of benefits and risks of chronic melanocortin-1 receptor activation

Abstract

The melanocortin-1 receptor (MC1R) is a G protein-coupled receptor that plays a pivotal role in human skin pigmentation, melanin synthesis, redox homeostasis and inflammation. Loss-of-function MC1R variants suppress G protein-coupled receptor coupling or cell surface expression leading to a decrease in adenyl cyclase activation and intracellular levels of cyclic adenosine monophosphate. Chronic activation of MC1R can occur in certain medical conditions such as Addison's disease and physiologic states such as pregnancy melasma. MC1R activation is more commonly caused by environmental exposure to ultraviolet (UV) radiation. Approved pharmacologic melanocortin agonists that activate MC1R signalling in a targeted manner or as a bystander effect have recently become available for erythropoietic protoporphyria, sexual desire disorders, monogenic obesity and syndromic obesity. Further, small peptide analogues of α-melanocortin-stimulating hormone, human MC1R selective agonists, are photoprotective, decreasing the adverse impact of UV radiation (a primary risk factor for skin cancer) and are being investigated as potential chemoprevention strategies. MC1R activation through induction of UV-protective skin pigmentation increased DNA repair, and control of aberrant cell growth may reduce the risk of melanoma but importantly does not prevent melanoma particularly in individuals with risk factors and regular skin examination remains critical in high-risk individuals.

FIGURE 1

Melanocortin signalling for melanin production and anti‐inflammatory effects in melanocytes., , , , α‐MSH, α–melanocortin‐stimulating hormone; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; ACTH, adrenocorticotropic hormone; CREB, cAMP response element–binding protein; DCT, dopachrome tautomerase; IκBα, NF‐κB inhibitor α; MC1R, melanocortin‐1 receptor; MITF, microphthalmia‐associated transcription factor; NF‐κB, nuclear factor κB; PC1, proprotein convertase 1; PC2, proprotein convertase 2; PKA, protein kinase A; POMC, proopiomelanocortin; ROS, reactive oxygen species; TNFα, tumour necrosis factor α; TNFRI, tumour necrosis factor receptor type I; TYR, tyrosinase; UV, ultraviolet.

FIGURE 2

MC1R signalling pathway during basal physiologic (left), hyperactivation (middle) and loss of function with UV radiation (right) conditions., , , , , , , , , , , , Thinner line widths indicate typical physiologic signalling, thicker lines indicate increased signalling and red x's indicate suppressed signalling. Larger eumelanin and pheomelanin ovals indicate higher protein synthesis, while smaller ovals indicate lower protein synthesis. Eumelanin and pheomelanin protein synthesis levels as compared to levels at MC1R basal activity are indicated as lower or higher by ‘<’ and ‘>’, respectively. α‐MSH, α–melanocortin‐stimulating hormone; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; BRAF, B‐Raf proto‐oncogene, serine/threonine kinase; CREB, cAMP response element–binding protein; ERK‐1/2, extracellular signal–regulated kinase 1 and 2; MC1R, melanocortin‐1 receptor; MEK, mitogen‐activated protein kinase kinase; MITF, microphthalmia‐associated transcription factor; pAkt, phospho‐Akt; PI3K, phosphatidylinositol 3‐kinase; PKA, protein kinase A; PIP₂, phosphatidylinositol 4,5‐bisphosphate; PIP₃, phosphatidylinositol 3,4,5‐trisphosphate; RAS, rat sarcoma; ROS, reactive oxygen species; TYR, tyrosinase; UV, ultraviolet.