Functionally divergent melanocortin receptor subtypes and the HPI axis in sea lamprey

The hypothalamic-pituitary-interrenal (HPI) axis is a highly conserved neuroendocrine system in vertebrates, but many details of its physiological role in jawless vertebrates remain unclear. Unlike the proopiomelanocortin (Pomc) gene of jawed vertebrates, lampreys have two divergent melanocortin prohormones, a proopiocortin (Poc) encoding adrenocorticotropic hormone (Acth) and promelanotropin (Pom) encoding two melanocyte-stimulate hormones (Msh-a and Msh-b). This study investigated the HPI axis in sea lamprey (Petromyzon marinus) by characterizing the potential involvement of key HPI components through gene expression analyses and functional studies. Phylogenetic analysis revealed that the two lamprey melanocortin receptors, Mcar and Mcbr, occupy basal positions relative to gnathostome melanocortin receptors. We observed tissue-specific transcriptional patterns of HPI axis genes, including that mcar and steroidogenic acute regulatory protein (star) are both expressed in a 'head kidney' region, suggesting a concomitant role in a corticosteroidogenic HPI axis. Both Mcar and Mcbr receptors can be activated by lamprey Acth, Msh-a, and Msh-b peptides. Notably, Mcar was more potently activated by Msh peptides over Acth, and neither receptor required the melanocortin receptor accessory protein (Mrap), which is required for gnathostome Mc2r function. These findings indicate that the strong selectivity for Acth and Mrap1-dependence of Mc2r may be derived traits that evolved after the agnathan-gnathostome divergence. Our results provide evidence for a functional HPI axis in lamprey, albeit with unique features compared to gnathostomes. This study offers insights into the evolutionary origins of the vertebrate HPI axis and highlights the need for further investigation into the regulation and physiological roles of the agnathan HPI axis.