Molecular and Cellular PharmacologyFunctional expression of Squalus acanthias melanocortin-5 receptor in CHO cells: Ligand selectivity and interaction with MRAP

The melanocortin-5 receptor (MC5) of the dogfish Squalus acanthias (SacMC5 receptor) can be functionally expressed in CHO cells in the absence of the co-expression of an exogenous MRAP cDNA. Both human ACTH(1-24) and dogfish ACTH(1-25) were much better stimulators of the SacMC5 receptor than any of the mammalian or dogfish MSH ligands that were tested. The order of ligand selectivity for the dogfish melanocortins was ACTH(1-25) > αMSH > γ-MSH = δ-MSH > β-MSH. Unlike mammalian MC5 receptors, the functional expression of the SacMC5 receptor was not negatively impacted when the receptor was co-expressed with a cartilaginous fish (Callorhinchus milii) MRAP2 cDNA. However, co-expression with either mouse mMRAP1 or zebrafish zfMRAP1 increased the sensitivity of SacMC5 receptor for hACTH(1-24) by at least one order of magnitude. Hence, SacMC5 receptor has the potential to interact with MRAP1 orthologs and in this regard behaved more like a melanocortin MC2 receptor ortholog than a melanocortin MC5 receptor ortholog. These observations are discussed in light of the evolution of the melanocortin receptor gene family in cartilaginous fish, and the physiological implications of these observations are considered.