Molecular evolution of GIP and Exendin and their receptors

Glucose-dependent insulinotropic polypeptide (GIP) is a product of the Gip gene and acts as an incretin hormone in mammals. Gip is most closely related to the proglucagon (Gcg) and Exendin genes and diverged from these very early in vertebrate evolution. In mammals, GIP acts through its specific receptor, encoded by the Gipr gene, which belongs to a subfamily of 7-transmembrane G-protein coupled receptor (GPCR) genes that also includes those for the proglucagon-derived peptides (Gcgr, Glp1r, and Glp2r), and the receptor for Exendin (Grlr). Gip, Gipr, Exendin, and Grlr genes are found in species from most vertebrate classes. While most species that have a Gip gene also have a Gipr gene, two classes of vertebrates, cartilaginous fish and birds, retain conserved Gip genes but lack Gipr genes. This raises the possibility the GIP signals through other receptors in some vertebrates. Exendin genes and the gene for its receptor, Grlr, are also found in diverse vertebrates, with the notable exception of mammals. Both GIP and Exendin likely have important roles in vertebrate physiology, but their roles are either dispensable or can be replaced by other hormones.