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Abstract
The glucagon (GCG) peptide family consists of GCG, glucagon-like peptide 1 (GLP1), and GLP2, which are derived from a common GCG precursor, and the glucose-dependent insulinotropic polypeptide (GIP). These peptides interact with cognate receptors, GCGR, GLP1R, GLP2R, and GIPR, which belong to the secretin-like G protein-coupled receptor (GPCR) family. We used bioinformatics to identify genes encoding a novel GCG-related peptide (GCRP) and its cognate receptor, GCRPR. The GCRP and GCRPR genes were found in representative tetrapod taxa such as anole lizard, chicken, and Xenopus, and in teleosts including medaka, fugu, tetraodon, and stickleback. However, they were not present in mammals and zebrafish. Phylogenetic and genome synteny analyses showed that GCRP emerged through two rounds of whole genome duplication (2R) during early vertebrate evolution. GCRPR appears to have arisen by local tandem gene duplications from a common ancestor of GCRPR, GCGR, and GLP2R after 2R. Biochemical ligand-receptor interaction analyses revealed that GCRP had the highest affinity for GCRPR in comparison to other GCGR family members. Stimulation of chicken, Xenopus, and medaka GCRPRs activated Gαs-mediated signaling. In contrast to chicken and Xenopus GCRPRs, medaka GCRPR also induced Gαq/11-mediated signaling. Chimeric peptides and receptors showed that the K16M17K18 and G16Q17A18 motifs in GCRP and GLP1, respectively, may at least in part contribute to specific recognition of their cognate receptors through interaction with the receptor core domain. In conclusion, we present novel data demonstrating that GCRP and GCRPR evolved through gene/genome duplications followed by specific modifications that conferred selective recognition to this ligand-receptor pair.
Highlights
Glucagon (GCG) and GCG-like peptides exhibit a variety of functions in the brain, gut, and endocrine tissues [1]
We examined the potency of GCG-related peptide (GCRP) to human GLP1R, GCGR, GLP2R, and GIPR in comparison with exendin4
HEK293T cells transfected with human GIPR, GLP1R, GLP2R, or GCGR were treated with GCRPs from three different species, exendin-4, and their corresponding ligand forms (Table 1)
Summary
Glucagon (GCG) and GCG-like peptides exhibit a variety of functions in the brain, gut, and endocrine tissues [1]. The GCG gene encodes a large GCG precursor, which undergoes tissuespecific posttranslational proteolytic processing to produce mature GCG, glucagon-like peptide 1 (GLP1), and glucagon-like peptide 2 (GLP2) [2,3,4]. The mature form of GCG is released from the pancreatic islets of Langerhans a cells in response to low blood glucose level. GLP1 and GLP2 are produced in the intestinal L-type endocrine cells in response to food ingestion. GLP1 stimulates insulin secretion from pancreatic b cells in a glucose-dependent manner [6,7]. GLP2 is a nutrient-responsive growth factor that stimulates specific trophic effects in the small and large intestines [8]. GLP1 and GIP are the main mammalian incretin hormones, accounting for approximately 50–70% of the total insulin secretion from pancreatic b cells [18]. GIP has been shown to promote bone formation by stimulating osteoblast proliferation and inhibiting apoptosis [19,20]
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