Fig. 2.

Signaling mechanisms of melanocortin 1 receptor (MC1R). MC1R couples to Gs stimulating cAMP/PKA and increasing intracellular Ca²⁺ levels. Ligand binding to MC1R promotes a cAMP-dependent activation of Rap1 and Ras, which leads to ERK1/2 phosphorylation through B-Raf signaling. By c-KIT transactivation, MC1R is also able to activate ERK1/2. β-arrestin 2 mediates MC1R internalization and desensitization, decreasing cAMP production but not affecting ERK1/2 activation. β-arrestin 1 competes with β-arrestin 2 for MC1R binding, which blocks β-arrestin 2-mediated cAMP inhibition. cAMP/PKA signaling increases synthesis of melanogenic pigments whereas ERK1/2 seems to have an inhibitory effect on this process. Akt/mTOR apparently increases cell survival during oxidative stress