The genes for the receptors for peptides similar to

The genes for the receptors for peptides similar to glucagon are dispersed on three human chromosomes, with two on chromosome 17 (GCGR and GLP2R) and one each on chromosomes 6 (GLP1R) and 19 (GIPR) (see Table S1). The exon–intron gene structures of these genes are similar, as are the genes for other secretin-like hormone receptors, with the protein-coding region distributed over 13 coding exons (Fig. 1). The structure of the GCGR and GIPR genes differ from those of the GLP1R and GLP2R by having an additional upstream exon that only contains 5′ untranslated sequence (Fig. 1). Introns between the coding exons are at very similar positions in the alignment of the receptor protein sequences, with the homologous introns interrupting the coding sequences in identical phases (Figs. 1 and S2). With the exception of the first and last coding exons, the lengths of the remaining coding exons are similar among the receptor genes (Table S2). In parallel with the identification of the orthologs of the Gila monster exendin gene, an additional glucagon receptor-like gene, the glucagon receptor-like receptor (Grlr, also called Gcglr and Gcrpr) was found in the genome sequence of many vertebrate species (Irwin and Prentice, 2011, Wang et al., 2012, Park et al., 2013). The initial study identifying this receptor gene (Irwin and Prentice, 2011) hypothesized that the product of the exendin ortholog should be the ligand for this receptor, with subsequent studies confirming this interaction (Wang et al., 2012, Park et al., 2013). The human genome, like that of other mammals with available genome sequences, does not contain a GRLR gene, and to date this gene has only been found in non-mammalian vertebrates (Irwin and Prentice, 2011, Wang et al., 2012, Park et al., 2013). The intron–exon structure of the Grlr gene, as well as the sizes of its coding exons, is similar to those for the genes for other receptors for peptides similar to glucagon (Fig. 1).
Receptors for peptides similar to glucagon and Class B1 of G-protein coupled receptors Receptors for peptides similar to glucagon encoded by GCG, GIP, and the ortholog of the Gila monster exendin gene are GPCRs, as are the receptors for many other secretin-like peptides. Specific receptors for secretin (SCTR), VIP (VPAC1 and VPAC2), GHRH (GHRHR) and PACAP (ADCYAP1R1) are all GPCRs (see Table S1) (Fredriksson et al., 2003, Fredriksson and Schiöth, 2005). The large GPCR gene family consists of at least 850 genes in mammals (Fredriksson et al., 2003, Fredriksson and Schiöth, 2005, Bjarnadóttir et al., 2006, Krishnan et al., 2013). Phylogenetic analyses of GPCR genes in a number of vertebrate species have consistently identified a subset of GPCRs, designated the Class B1 GPCRs, which include the receptors for the secretin-like peptides described above as well as receptors for corticotropin releasing hormone (CRHR1 and CRHR2), parathyroid (PTH1R and PTH2R), 740 Y-P (CALCR) and a calcitonin receptor-like gene (CALCRL) (Harmar, 2001, Fredriksson et al., 2003, Fredriksson and Schiöth, 2005, Mayo et al., 2003, Gloriam et al., 2007, Krishnan et al., 2013). Phylogenies of the nucleotide or amino acid sequences of these receptors consistently group the receptors for the secretin-like hormones as a monophyletic group with CRHR1, CRHR2, CALCR, and CALCRL being the most closely related sister groups (Cardoso et al., 2005, Cardoso et al., 2006, Ng et al., 2010, Tam et al., 2011, Park et al., 2013). The phylogeny of the secretin hormone-like receptors typically separate into two monophyletic groups: genes for the receptors for proglucagon-derived peptides (GCGR, GLP1R and GLP2R) and GIP (GIPR) forming one group; and genes for the receptors for the other secretin-like hormones (SCTR, GHRHR, VIPR1, VIPR2, and ADCYAP1R1) forming a second group (Cardoso et al., 2005, Cardoso et al., 2006, Ng et al., 2010, Tam et al., 2011, Park et al., 2013). In Fig. 2 the phylogenetic relationships of the human genes for receptors for secretin-like hormones, along with the chicken gene for the receptor for the exendin homolog, is illustrated (see Table S1 for source of data, Fig. S3 for the DNA sequence alignment, and Fig. S4 for the tree generated by the maximum likelihood method in Newick format). Phylogenies generated by both Bayesian and maximum likelihood methods (see Figs. 2 and S4) confidently grouped the receptors for the proglucagon-derived peptides, and GIP, and yielded strong support for a second group that included all of the other secretin-like hormones. The chicken Grlr gene also confidently groups with the receptors for the proglucagon-derived peptides and GIP, in agreement with previous studies (Irwin and Prentice, 2011, Park et al., 2013). The gene for the GIP receptor (GIPR) is most closely related (and thus have shared the most recent common ancestry) to the glucagon receptor gene (GCGR), with more ancient divergences from this pair leading to Grlr, GLP1R, and GLP2R (Figs. 2 and S4). The phylogeny in Fig. 2 implies that the receptor genes diverged in a step-wise fashion with a gene for the GLP-2 receptor diverging first, followed by the divergence of genes for the GLP-1 receptor, then a gene for the receptor of the exendin ortholog, and finally the divergence of the genes for the GIP and glucagon receptors. Earlier studies had concluded that the relationships among the genes for the receptors did not mirror the phylogenetic relationships of the proglucagon-derived peptides and GIP (Irwin, 2005, Irwin, 2010), where GLP-1 and GLP-2 were most closely related, with glucagon and GIP diverging earlier (Irwin et al., 1999, Ng et al., 2010, Cardoso et al., 2010). However, it must be cautioned, as mentioned above, that phylogenies generated for short peptides often cannot be confidently resolved (Dores et al., 1996), and interestingly, a recent phylogenetic analysis (Irwin, 2012) that included diverse secretin-like hormones including GIP and exendin homologs, from mammals, birds and reptiles yielded a phylogeny (see Fig. S1) that almost mirrored the receptor phylogeny shown in Fig. 2.