Biased signaling in fish melanocortin-4 receptors (MC4Rs): Divergent pharmacology of four ligands on spotted scat (Scatophagus argus) and grass carp (Ctenopharyngodon idella) MC4Rs

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The melanocortin-4 receptor (MC4R) plays a critical role in the regulation of energy homeostasis in both mammals and fish. Several fish MC4Rs recently characterized have high constitutive activities, potentially associated with food intake and growth rate. In the present study, we systematically investigated the effects of four human MC4R (hMC4R) antagonists, including agouti-related peptide (AgRP), Ipsen 5i, ML00253764, and MCL0020, on the cAMP and ERK1/2 signaling of two fish MC4Rs: spotted scat (Scatophagus argus) MC4R (saMC4R) and grass carp (Ctenopharyngodon idella) MC4R (ciMC4R), with hMC4R as a control. We showed that both saMC4R and ciMC4R were constitutively active with significantly increased basal cAMP levels. AgRP acted as an inverse agonist in cAMP signaling pathway in both fish MC4Rs whereas MCL0020 functioned as an inverse agonist for ciMC4R but a weak neutral antagonist for saMC4R. Ipsen 5i and MCL0020 behaved as neutral allosteric modulators in the cAMP signaling of fish MC4Rs. The saMC4R and ciMC4R had similar basal pERK1/2 levels as hMC4R and the pERK1/2 levels of the two fish MC4Rs were significantly increased upon stimulation with all four ligands. In summary, our studies demonstrated the existence of biased signaling in fish MC4R. We also showed dramatic pharmacological differences of human and fish MC4Rs with synthetic ligands. Our data provided novel insights and led to a better understanding of fish MC4R pharmacology.