Melanocortin receptors (MCR), which belong to the superfamiliy of G protein-coupled receptors (GPCR), are preferentially coupled to Gs proteins and play a major role in the regulation of energy homeostasis. In line with this notion, mutations in the MC4R gene are the most frequent monogenic cause of severe obesity in human beings. Recently it has been shown that the MC4R receptor undergoes, similar to most GPCR, GPCR kinase (GRK) and arrestin-mediated ligand-promoted receptor endocytosis. The MC4R-D90N mutation, which has also been isolated from an obese individual, binds agonists with unchanged high affinity, but promotes no detectable activation of the Gs signalling pathway in HEK-293 cells. Despite of the blunted Gs signalling, agonist binding to the MC4R-D90N mutant induced the recruitment of the adapter protein arrestin when both proteins were overexpressed in HEK-293 cells as monitored by the bioluminescence resonance energy transfer technique in living cells, indicating that activation of the GRK/arrestin pathway does not require Gs signalling. However, despite of the key role arrestins play in regulating ligand-promoted receptor endocytosis, arrestin recruitment to the Gs signalling deficient MC4R-D90N variant was not sufficient to induce receptor endocytosis. These data indicate that although arrestin recruitmnet to the MC4R occurs independently of Gs signalling, ligand-promoted MC4R endocytosis requires the activation of Gs proteins, suggesting that so far unknown Gs signalling-dependent mechanism are involved in regulating ligand- promoted MC4R endocytosis.