Schematical overview of the signaling pathway mediated by MC1R

Schematical overview of the signaling pathway mediated by MC1R. MC1R resides at the plasma membrane of melanocytes and is activated by melanocortins, in particular α-MSH, and inactivated by Agouti protein. To be fully effective, Agouti also needs Attractin, which helps Agouti binding to the receptor, and Mahogunin, which acts at the cytosolic side of the plasma membrane, most likely by competing with Gs for receptor binding. In addition, MC1R has a neutral agonist, β-Defensin, which interferes with both agonist and antagonist binding, thereby highlighting the high degree of constitutive activity of the receptor. The canonical pathway activated by MC1R leads to cAMP increase via Gs and adenylyl cyclase, and proceeds with CREB phosphorylation by PKA and transcription of downstream targets, in particular MITF. Increased MITF activity is further reinforced and regulated by cAMP-independent ERK activation, probably resulting from cross-talk between MC1R and the cKIT receptor. MITF binds to promoters and stimulates transcription of genes coding for melanosomal proteins implicated in the eumelanogenesis pathway, thus inducing a switch from pheomelanin to eumelain synthesis and increasing melanosome number, size and transport. MC1R signaling also reduces the generation of reactive oxygen species and enhances DNA repair mechanisms by still poorly understood mechanisms (not shown). PM, plasma membrane.

Publication

SIGNALING PATHWAYS IN MELANOSOME BIOGENESIS AND PATHOLOGY. () Maria Vittoria Schiaffino. Int J Biochem Cell Biol. ;42(7):1094-1104. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

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