Views on the co-evolution of the melanocortin-2 receptor, MRAPs, and the hypothalamus/pituitary/adrenal-interrenal axis

• The evolution of the HPA-I axis is intertwined with the co-evolution of the MRAPs and MC2R.
• The putative HPI axis in cartilaginous fishes appears to be MRAP independent.
• The MC2R ortholog in the HPA-I axis of teleost and tetrapods is MRAP dependent.
• The transition to a MRAP dependent HPI axis occurred in the ancestral bony fishes.

A critical regulatory component of the hypothalamus/pituitary/adrenal axis (HPA) in mammals, reptiles and birds, and in the hypothalamus/pituitary/interrenal (HPI) axis of amphibians and teleosts (modern bony fishes) is the strict ligand selectivity of the melanocortin-2 receptor (MC2R). Tetrapod and teleost MC2R orthologs can only be activated by the anterior pituitary hormone, ACTH, but not by any of the MSH-sized ligands coded in POMC. In addition, both tetrapod and teleost MC2R orthologs require co-expression with the accessory protein, MRAP. However, the MC2R ortholog of the elephant shark, a cartilaginous fish, can be activated by either ACTH or the MSH-sized ligands, and the elephant shark MC2R ortholog does not require co-expression with an MRAP for activation. Given these observations, this review will provide a scenario for the co-evolution of MC2R and MRAP, based on the assumption that the obligate interaction between MC2R and MRAP evolved during the early radiation of the ancestral bony fishes.