Evolution of receptors for proglucagon-derived peptides: isolation of frog glucagon receptors.
The mammalian proglucagon gene encodes three glucagon-like sequences, glucagon, glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2). Each of these three functionally distinct proglucagon-derived peptides has a unique, but related, receptor. To better understand the origin of the unique physiological functions of each proglucagon-derived glucagon-like sequence we have cloned glucagon-like receptors from two species of frogs, Xenopus laevis and Rana pipiens. The cloned glucagon-like receptor sequences were found to be most closely related to glucagon receptors. To determine whether the evolutionary history of the receptors for proglucagon-derived peptides was the same as that inferred for the peptide hormones, we conducted a phylogenetic analysis using both parsimony and distance methods. We show that the evolutionary history of the receptors for glucagon-like sequences differ from the history of the glucagon-like sequences. The phylogeny of receptors for proglucagon-derived peptides is not monophyletic (i.e. they are not each other's closest relatives), as the receptor for the hormone glucose-dependent insulinotropic peptide (GIP) is more closely related to the glucagon receptor than either the GLP-1 or GLP-2 receptors. In contrast to the evolutionary origin of glucagon-like sequences, where glucagon is of most ancient origin, we found that the GLP-2 receptor has the most ancient origin. These observations suggest that the diversification of the glucagon-like sequences encoded by the proglucagon gene and of the receptors for these peptides occurred independently, and that either these hormones or their receptors have been recruited for new functions.
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 100 College St., Toronto, Ontario, Canada, M5G 1L5.
P
P
Sivarajah
M B
MB
Wheeler
D M
DM
Irwin
D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D017931:DNA Primers / Q000737:chemistry; D019143:Evolution, Molecular; D005934:Glucagon / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D052336:Proglucagon; D011498:Protein Precursors / Q000235:genetics*; D012313:RNA / Q000378:metabolism; D011894:Rana pipiens / Q000235:genetics*; D051381:Rats; D018027:Receptors, Glucagon / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012633:Secretin / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis / Q000235:genetics*
D017931:DNA Primers; D011498:Protein Precursors; D018027:Receptors, Glucagon; D012633:Secretin; D052336:Proglucagon; D012313:RNA; D005934:Glucagon