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

• Published in: Molecular and cellular endocrinology Vol. 408; pp. 12 - 22
• Main Authors: Dores, Robert M., Garcia, Yesenia
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 15.06.2015
• Subjects: Amino Acid Sequence; Animals; Evolution, Molecular; HPA; HPI; Humans; Hypothalamo-Hypophyseal System - metabolism; Kidney - metabolism; MC2R; MC5R; Membrane Proteins - genetics; Molecular Sequence Data; MRAP; MRAP2; Pituitary-Adrenal System - metabolism; Receptor, Melanocortin, Type 2 - genetics; MRAP; HPI; HPA; MC2R; MRAP2; MC5R
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2014.12.022

•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.