The GTPase-activating protein-related domain of neurofibromin interacts with MC1R and regulates pigmentation-mediated signaling in human melanocytes

The melanocortin 1 receptor (MC1R) is a G-protein coupled (GPCR) which plays major role in controlling melanogenesis. A large body of evidence indicates that GPCRs are part protein complexes critical for their signal transduction properties. Among proteins may affect MC1R signaling, neurofibromin (Nf1), GTPase activating (GAP) Ras, special interest as it regulates adenylyl cyclase activity and ERK two pathways involved signaling. Moreover, mutations this gene encoding Nf1 responsible neurofibromatosis type I, disease inducing hyperpigmented flat skin lesions. Using co-immunoprecipitation Bioluminescence Resonance Energy Transfer experiments we demonstrated physical interaction with MC1R. In particular, the GAP domain directly constitutively interacts melanocytes. Pharmacologic genetic approaches revealed important to regulate intracellular signaling melanogenesis and, consequently, melanogenic enzyme expression melanin production. These finding shed new light on understanding cure pigmentation disorders.