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    • Receptors for glucagon Gcgr GLP Glp r and GLP Glp

    2021-09-08

    Receptors for glucagon (Gcgr), GLP-1 (Glp1r), and GLP-2 (Glp2r) are G-protein coupled receptors (GPCRs) belonging to class B-1 (secretin receptor-like) family of GPCRs (Harmar, 2001, Fredriksson et al., 2003). The mammalian Gcgr, Glp1r, and Glp2r genes, together with the px12 for the receptors for two other peptides similar to glucagon, GIP (Gipr) and the Exendin-like peptide (grlr, also called gcglr and gcrpr) comprise a subfamily of the class B-1 receptors (Cardoso et al., 2005, Cardoso et al., 2006, Cardoso et al., 2018, Ng et al., 2010, Tam et al., 2011, Park et al., 2013, Irwin, 2014). In mammals, the receptors for glucagon, GLP-1, and GLP-2 are highly specific only towards their native ligands (Mayo et al., 2003). glp2rs have not been functionally characterized in other vertebrates. The ligand specificity of Gcgr in teleost fish (Carassius auratus) (Chow et al., 2004) and frogs (Rana tigrina regulosa) (Ngan et al., 1999) is similar to their mammalian orthologs, i.e., they bind only glucagon and not GLP-1. The receptor that is specific for GLP-1 has been lost on the ray-finned fish lineage (Irwin and Wong, 2005, Ng et al., 2010, Irwin, 2014). Instead, GLP-1 binds to a receptor that has dual ligand selectivity towards both glucagon and GLP-1 (Mojsov, 2000, Yeung et al., 2002, Oren et al., 2016). Fish are important models for understanding biology, which have led to breakthroughs that impact human medicine (Conlon, 2000, Polakof et al., 2011a, Schartl, 2014). Indeed, it was the initial cloning of the gcg gene in a fish (American anglerfish (Lund et al., 1982, Lund et al., 1983)) that led to the discovery of GLP-1 (Mojsov et al., 1986, Orskov et al., 1986), a hormone that is now used as an important therapeutic agent in the treatment of diabetes (Estall and Drucker, 2006, Campbell and Drucker, 2013). As the numbers of species with genome sequences continues to increase (Meadows and Lindblad-Toh, 2017), we sought to determine when the duplicate proglucagon and glucagon receptor genes originated in fish, their phylogenetic distribution, and to conduct a comparative analysis of their sequences to identify difference in the evolutionary profiles of these sequences. These analyses should help determine which peptides within the proglucagon sequences, and portions within the receptor sequences, play important and unique aspects in the regulation of metabolism in fish and vertebrates.
    Materials and methods
    Results and discussion
    Conclusions After the fish-specific genome duplication, the most common fate of duplicated genes was the loss of one paralog, with fewer than 20% being retained as duplicates (Pasquier et al., 2017). Reasons for retaining duplicated genes include: subfunctionalization, i.e., paralogs retain some of the functions of the ancestor, but only together retain all; neofunctionalization, i.e., one copy acquiring a new function; and dosage, i.e., increased yield of a gene product from two similar copies is beneficial (Glasauer and Neuhauss, 2014). Duplicated genes for both proglucagon (gcga and gcgb) and the glucagon receptor (gcgra and gcgrb) have been retained in all teleost fish genomes that have been examined (Fig. 1 and Supplementary Table S1). Both proglucagon and the glucagon receptors likely have been retained through a combination of both subfunctionalization and neofunctionalization. The acquisition of the ability of Gcgrb to bind and be activated by GLP-1 (Mojsov, 2000, Yeung et al., 2002, Oren et al., 2016) is a clear example of neofunctionalization as it has acquired a new biological function, for example in regulating glucose metabolism in the liver (Mommsen and Moon 1990), intestine (Soengas and Moon, 1998, Polakof et al., 2010), brain (Silverstein et al., 2001), and through the gut-brain axis (Polakof et al., 2011b). However, as Gcgrb retains the ability to be bound and activated by glucagon (Yeung et al., 2002, Oren et al., 2016) this could suggest that Gcgra is redundant. The observations that glucagon and GLP-1 have similar, but not identical physiological action in fish (Mommsen et al., 1987, Mommsen and Moon, 1990, Plisetskaya and Mommsen, 1996) suggests that Gcgra might still have roles that are not fulfilled by Gcgrb and implies that some subfunctionalization in the roles of gcgra and gcgrb has occurred since duplication of the ancestral gene and represents an adaptation of vertebrate glucose metabolism to the diverse life histories of fish. The existence of two gluco-regulatory receptors in fish liver may especially be beneficial during the seasonal variation in the circulating levels of glucagon and GLP-1 and variation of metabolic responses of hepatocytes to glucagon and GLP-1 (Mommsen and Moon, 1989, Plisetskaya et al., 1989). During different seasons glucagon can continue to regulate glucose metabolism through regulatory pathways that are integrated through either Gcgra or Gcgrb or both receptors. Gcgrb may still have a role that is not fulfilled by Gcgra, for example in regulating GLP-1 effects on the feeding behavior (Silverstein et al., 2001) and through the gut-brain axis (Polakof et al., 2011b).