Evolution of receptors for peptides similar to glucagon.

The genes encoding the peptide precursors for glucagon (GCG), glucose-dependent insulinotropic peptide (GIP), and ortholog of exendin belong to the same family as shown by sequence similarity. The peptides similar to glucagon encoded by these genes signal through a closely related subfamily of G-protein coupled receptors. A total of five types of genes for receptors for these peptides have been identified, three for the products of GCG (GCGR, GLP1R, and GLP2R) and one each for the products of GIP (GIPR) and the ortholog of exendin (Grlr). Phylogenetic and genomic neighborhood analyses clearly show that these genes originated very early in vertebrate evolution and all were present in the common ancestor of tetrapods and bony fish. Despite their ancient origins, some of these genes are dispensable, with the Glp1r, Gipr, and Grlr being lost on the lineages leading to bony fish, birds, and mammals, respectively. The loss of the genes for these receptors may have been driving forces in the evolution of new functions for these peptides similar to glucagon.