title: Evolution of new hormone function: loss and gain of a receptor.
abstract: The vertebrate proglucagon gene encodes three glucagon-like sequences (glucagon, glucagon-like peptide-1 [GLP-1], and glucagon-like peptide 2 [GLP-2]) that have distinct functions in regulating metabolism in mammals. In contrast, glucagon and GLP-1 have similar physiological actions in fish, that of mammalian glucagon. We have identified sequences similar to receptors for proglucagon-derived peptides from the genomes of two fish (pufferfish and zebrafish), a frog (Xenopus tropicalis), and a bird (chicken). Phylogenetic analysis of the receptor sequences suggested an explanation for the divergent function of GLP-1 in fish and mammals. The phylogeny of our predicted and characterized receptors for proglucagon-derived peptides demonstrate that receptors for glucagon, GLP-1, and GLP-2 have an origin before the divergence of fish and mammals; however, fish have lost the gene encoding the GLP-1 class of receptors, and likely the incretin action of GLP-1. Receptors that bind GLP-1, but yield glucagon-like action, have been characterized in goldfish and zebrafish, and these sequences are most closely related to glucagon receptors. Both pufferfish and zebrafish have a second glucagon receptor-like gene that is most closely related to the characterized goldfish glucagon receptor. The phylogeny of glucagon receptor-like genes in fish indicates that a duplication of the glucagon receptor gene occurred on the ancestral fish lineage, and could explain the shared action of glucagon and GLP-1. We suggest that the binding specificity of one of the duplicated glucagon receptors has diverged, yielding receptors for GLP-1 and glucagon, but that ancestral downstream signaling has been maintained, resulting in both receptors retaining glucagon-stimulated downstream effects.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, Banting and Best Diabetes Centre, University of Toronto, 100 College St., Toronto, Ontario, Canada M5G lL5. david.irwin@utoronto.ca
authors.forename: D M
authors.initials: DM
authors.lastname: Irwin
authors.forename: K
authors.initials: K
authors.lastname: Wong
mesh_terms: D000818:Animals; D002645:Chickens; D019143:Evolution, Molecular; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000502:physiology; D053767:Glucagon-Like Peptide 2; D004763:Glucagon-Like Peptides / Q000235:genetics* / Q000502:physiology; D008957:Models, Genetic; D010802:Phylogeny; D018027:Receptors, Glucagon / Q000235:genetics* / Q000502:physiology; D023741:Takifugu; D014981:Xenopus; D015027:Zebrafish
chemical_list: D053767:Glucagon-Like Peptide 2; D018027:Receptors, Glucagon; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1