title: Molecular evolution of GPCRs: Melanocortin/melanocortin receptors.
abstract: The melanocortin receptors (MCRs) are a family of G protein-coupled receptors that are activated by melanocortin ligands derived from the proprotein, proopiomelanocortin (POMC). During the radiation of the gnathostomes, the five receptors have become functionally segregated (i.e. melanocortin 1 receptor (MC1R), pigmentation regulation; MC2R, glucocorticoid synthesis; MC3R and MC4R, energy homeostasis; and MC5R, exocrine gland physiology). A focus of this review is the role that ligand selectivity plays in the hypothalamus/pituitary/adrenal-interrenal (HPA-I) axis of teleosts and tetrapods as a result of the exclusive ligand selectivity of MC2R for the ligand ACTH. A second focal point of this review is the roles that the accessory proteins melanocortin 2 receptor accessory protein 1 (MRAP1) and MRAP2 are playing in, respectively, the HPA-I axis (MC2R) and the regulation of energy homeostasis by neurons in the hypothalamus (MC4R) of teleosts and tetrapods. In addition, observations are presented on trends in the ligand selectivity parameters of cartilaginous fish, teleost, and tetrapod MC1R, MC3R, MC4R, and MC5R paralogs, and the modeling of the HFRW motif of ACTH(1-24) when compared with α-MSH. The radiation of the MCRs during the evolution of the gnathostomes provides examples of how the physiology of endocrine and neuronal circuits can be shaped by ligand selectivity, the intersession of reverse agonists (agouti-related peptides (AGRPs)), and interactions with accessory proteins (MRAPs).
authors.affiliation: Department of Biological SciencesUniversity of Denver, Denver, Colorado 80210, USADepartment of BiologyUniversity of Akron, Akron, Ohio 44325, USA rdores@du.edu.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Dores
authors.affiliation: Department of Biological SciencesUniversity of Denver, Denver, Colorado 80210, USADepartment of BiologyUniversity of Akron, Akron, Ohio 44325, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Londraville
authors.affiliation: Department of Biological SciencesUniversity of Denver, Denver, Colorado 80210, USADepartment of BiologyUniversity of Akron, Akron, Ohio 44325, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Prokop
authors.affiliation: Department of Biological SciencesUniversity of Denver, Denver, Colorado 80210, USADepartment of BiologyUniversity of Akron, Akron, Ohio 44325, USA.
authors.forename: Perry
authors.initials: P
authors.lastname: Davis
authors.affiliation: Department of Biological SciencesUniversity of Denver, Denver, Colorado 80210, USADepartment of BiologyUniversity of Akron, Akron, Ohio 44325, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Dewey
authors.affiliation: Department of Biological SciencesUniversity of Denver, Denver, Colorado 80210, USADepartment of BiologyUniversity of Akron, Akron, Ohio 44325, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Lesinski
mesh_terms: D000311:Adrenal Glands / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D004734:Energy Metabolism; D019143:Evolution, Molecular; D005088:Exocrine Glands / Q000502:physiology; D005399:Fishes / Q000235:genetics* / Q000378:metabolism; D005938:Glucocorticoids / Q000096:biosynthesis; D007031:Hypothalamus / Q000502:physiology; D053486:Melanocortins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010858:Pigmentation / Q000502:physiology; D010902:Pituitary Gland / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000235:genetics*
chemical_list: D005938:Glucocorticoids; D053486:Melanocortins; D044101:Receptors, Melanocortin; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone
keywords: ACTH; MC2R; MC4R; MRAP1; MRAP2; melanocortin peptides; melanocortin receptors; α-MSH