Agonist‐independent, high constitutive activity of the human mela‐nocortin 1 receptor

Abstract

The melanocortin hormones act on epidermal melanocytes to increase eumelanogenesis, melanocyte dendricity and likely melanosome transfer to keratinocytes. These actions are mediated by the melanocortin 1 receptor (MC1R), positively coupled to adenylyl cyclase. Gain‐of‐function Mc1r alleles are associated with dark, eumelanic skin. Conversely, loss‐of‐function variants or overexpression of agouti, the natural antagonist, yield yellow, pheomelanic furs. In humans, loss‐of‐function MC1R variants are associated with fair skin, poor tanning and increased skin cancer risk. Therefore, MC1R is a key regulator of mammalian pigmentation. An induction of constitutive pigmentation in amelanotic mouse melanoma cells following the expression of MC1R has been reported, suggesting that this receptor might display agonist‐independent activity, although this aspect has not yet been comparatively studied for MC1R and Mc1r. We show that the expression of MC1R in heterologous systems leads to high agonist‐independent increases in intracellular cAMP. This basal signalling is a function of the quantity of receptor expressed, is considerably higher for MC1R than Mc1r and is also observed in human melanoma cells overexpressing MC1R. Moreover, MC1R basal signalling is abolished or reduced by point mutations impairing the response to agonists. Lastly, the expression of wild‐type MC1R, but not of loss‐of‐function mutants potently stimulates forskolin activation of adenylyl cyclase, a feature characteristic of constitutively active G‐coupled receptors. Therefore, we conclude that MC1R displays a strong agonist‐independent constitutive activity.