Observations on the ligand selectivity of the melanocortin 2 receptor

The melanocortin 2 receptor (MC2R) is unique in terms of ligand selectivity and in vitro expression in mammalian cell lines as compared to the other four mammalian MCRs. It is well established that ACTH is the only melanocortin ligand that can activate the ACTH receptor (i.e., melanocortin 2 receptor). Recent studies have provided new insights into the presence of a common binding site for the HFRW motif common to all melanocortin ligands. However, the activation of the melanocortin 2 receptor requires an additional amino acid motif that is only found in the sequence of ACTH. This mini-review will focus on these two topics and provide a phylogenetic perspective on the evolution of MC2R ligand selectivity.

► ACTH emerged as the exclusive ligand for MC2R after the divergence of the cartilaginous and bony fishes. ► ACTH(1–39) requires MRAP1 for trafficking to the plasma membrane. ► ACTH(1–39) requires MRAP1 for functional expression.