The role of accessory proteins and co-factors in regulation of melanocortin-4 receptor signalling: An update

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor with an essential role in appetite suppression and energy homeostasis. Genetic mutations in the receptor and components of its signalling pathway that cause obesity in humans, dogs and rodent models have revealed important insights into how the receptor signals and what regulates its cell surface expression. Structural studies have identified calcium as a critical cofactor for agonist binding and receptor function, while several transmembrane proteins have been shown to modulate MC4R activity. Here, we describe recent developments in our understanding of how accessory proteins and cofactors, identified using genomic approaches and screens for protein interaction, modify MC4R trafficking and signalling. We discuss how signalling by G_s and G_q/11 pathways may have differential effects on food intake, weight gain and cardiovascular function. We also summarise recent studies of MC4R expression at primary cilia, receptor oligomerisation, newly identified proteins that regulate MC4R cell surface expression, and briefly discuss novel endogenous agonists.