ACTH, Melanocortin Receptors, and MRAP Accessory Proteins

The evolution of the pituitary hormone, ACTH, the melanocortin receptors, a family of G protein-coupled receptors, and the melanocortin receptor accessory proteins, MRAP1 and MRAP2, are intertwined, and parallel the evolution of the chordates. While all melanocortin-related peptides (i.e., ACTH, αMSH, βMSH, γMSH, δMSH) have the canonical HFRW amino acid motif required for activation of melanocortin receptors (i.e., MC1R, MC2R, MC3R, MC4R, MC5R), during the radiation of the gnathostomes (jawed vertebrates) the ligand selectivity of melanocortin-2 receptor orthologs has diverged between cartilaginous fishes and bony vertebrates in a manner that has implications for the Hypothalamus/Pituitary/Adrenal-Interrenal axis.