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  • Phylogenetic analysis of the secretin like hormones yields p

    2021-10-11

    Phylogenetic analysis of the secretin-like hormones yields poorly supported trees due to the short length of their peptide sequences (Dores et al., 1996). However, phylogenetic analyses typically show that the secretin-like peptides encoded by the proglucagon (glucagon, GLP-1 and GLP-2) and GIP SB 203580 hydrochloride are most closely related (Hoyle, 1998, Irwin et al., 1999, Cardoso et al., 2010, Ng et al., 2010, Irwin, 2012) (see Fig. S1). Exendin-1 and -2, from the Gila monster, are most similar to GLP-1, while exendin-3 and -4 are very divergent and more similar to other secretin-like hormones (Hoyle, 1998, Sherwood et al., 2000, Fry et al., 2010). Comparison of the exendin-1 and -4 precursor sequences, although, showed that the non-hormone portion of the precursors (signal and N-terminal pro-peptide sequences) are very similar (Pohl and Wank, 1998). These observations suggested that the exendin peptides experienced convergent evolution, with some of the exendin sequences evolving to be more similar to either GLP-1 or VIP (Fry et al., 2010). The inclusion of putative orthologs of the exendin peptides (from other reptiles and birds) into phylogenetic analyses of secretin-like peptides allowed a better resolution of the relationships of exendin to the other secretin-like peptides revealing that exendin is most closely related to the proglucagon-derived peptides and GIP (Irwin and Prentice, 2011, Irwin, 2012, Wang et al., 2012, Park et al., 2013) (see Fig. S1). This recent phylogenetic analysis of secretin-like peptides concludes that exendin-1 and -2 evolved convergently upon the VIP sequence (Irwin, 2012). The close relationship of the exendin, GCG, and GIP genes was strengthened by the observation that the genomic location of the exendin ortholog is similar to those for the GCG and GIP genes (Irwin and Prentice, 2011, Irwin, 2012, Wang et al., 2012, Park et al., 2013). These observations suggest that GCG, GIP, and the gene for the exendin ortholog represent three of the four genes generated during the pair of genome duplications that occurred on the ancestral vertebrate lineage (Irwin and Prentice, 2011, Irwin, 2012, Wang et al., 2012). The remaining genes encoding the secretin-like sequences are not found in similar genomic neighborhoods, consistent with a conclusion that the GCG, GIP, and exendin ortholog genes are more closely related to each other than they are to any of the other secretin-like genes (Irwin and Prentice, 2011).
    Genes for the receptors for peptides similar to glucagon Proglucagon-derived peptides and other secretin-like hormones exert their physiological effects through binding to specific receptors found on the surfaces of cells in the target tissues. A cDNA clone for a specific receptor for the GLP-1 receptor (GLP1R) was cloned in 1992 and found to encode a G-protein coupled receptor (GPCR) (Thorens, 1992). Receptors for the other two glucagon-like peptides encoded by GCG, glucagon (GCGR) and GLP-2 (GLP2R), are also G-protein coupled receptors (Jelinek et al., 1993, Munroe et al., 1999), as are the receptors for the peptide similar to glucagon encoded by the GIP gene (GIPR; Usdin et al., 1993) and the putative ortholog of Gila monster exendin (GRLR, Irwin and Prentice, 2011; also called GCGLR, Wang et al., 2012; and GCRPR, Park et al., 2013). The genes for each of these receptors are expressed in a tissue-specific manner, with high expression in the physiologically relevant tissues (i.e., tissues where the hormones have known or predicted physiological action). While the function of the ortholog of exendin is currently unknown, the observation that the Grlr gene is most abundantly expressed in the brain (Irwin and Prentice, 2011, Wang et al., 2012) suggests that the likely physiological target of the exendin ortholog is in the brain, however, this still leaves a long list of potential functions. The discovery that GLP1R and GLP2R are also expressed in portions of the brain (Alvarez et al., 1996, Lovshin et al., 2004) prompted searches for additional functions for these peptides. Receptors for the peptides similar to glucagon range in size from about 400 to 550 amino acids in length, with GIPR being shortest and GLP2R being longest (see Figs. 1 and S2). Alignment of the protein sequences of these receptors show that the sequences show similarity across most of their length, with the regions encoding the seven transmembrane domain regions being well-conserved, as are the distances between these seven domains, whereas the N-terminal and C-terminal regions show greater variability both in length and in their sequences (see Figs. 1 and S2).