J-L HWANG and others Evolution of GLP1 and GLP1 52:3 T15–T27 Thematic Review receptor MOLECULAR EVOLUTION OF GPCRS GLP1/GLP1 receptors Correspondence Jong-Ik Hwang, Seongsik Yun, Mi Jin Moon, Cho Rong Park and Jae Young Seong should be addressed to J Y Seong Graduate School of Medicine, Korea University, Seoul 136-705, Republic of Korea Email [email protected] Abstract Glucagon-like peptide 1 (GLP1) is an intestinal incretin that regulates glucose homeostasis Key Words through stimulation of insulin secretion from pancreatic b-cells and inhibits appetite by " evolution acting on the brain. Thus, it is a promising therapeutic agent for the treatment of type 2 " exon diabetes mellitus and obesity. Studies using synteny and reconstructed ancestral " GLP1 chromosomes suggest that families for GLP1 and its receptor (GLP1R) have emerged through " GLP1R two rounds (2R) of whole genome duplication and local gene duplications before and after " G protein-coupled receptor 2R. Exon duplications have also contributed to the expansion of the peptide family " genome members. Specific changes in the amino acid sequence following exon/gene/genome " gene duplications have established distinct yet related peptide and receptor families. These " duplication specific changes also confer selective interactions between GLP1 and GLP1R. In this review, we present a possible macro (genome level)- and micro (gene/exon level)-evolution mechanisms of GLP1 and GLP1R, which allows them to acquire selective interactions between this ligand–receptor pair. This information may provide critical insight for the Journal of Molecular development of potent therapeutic agents targeting GLP1R. Endocrinology Journal of Molecular Endocrinology (2014) 52, T15–T27 Introduction Glucagon-like peptide 1 (GLP1) is a gastrointestinal 1990). GLP1, secreted from L-cells in response to food peptide hormone that stimulates insulin secretion from intake, regulates blood glucose level by inducing insulin pancreatic b-cells and promotes insulin synthesis secretion in a glucose concentration-dependent manner, (Schmidt et al. 1985, Fehmann & Habener 1992, Moon while it suppresses GCG release from pancreatic a-cells et al. 2011). GLP1, encoded by the glucagon (GCG) gene, is (Fehmann et al. 1995, Hansotia & Drucker 2005). The produced by tissue-specific posttranslational proteolytic glucose-dependent action of GLP1 has potential for the processing of a large precursor containing three indepen- treatment of diabetes mellitus because it does not cause dent peptides GCG, GLP1, and GLP2 (Mojsov et al. 1986, hypoglycemia under normal plasma glucose concen- Kieffer & Habener 1999). Intestinal L-cells produce mature tration conditions (Baggio & Drucker 2002, Nauck et al. GLP1 and GLP2 but not GCG, while pancreatic a-cells 2002). In addition to its incretin activity, GLP1 stimulates produce mature GCG but not GLP1 and GLP2. Biologically proliferation and differentiation of pancreatic b-cells active GLP1s consist of 30 or 31 amino acids, both of (Xu et al. 1999, Drucker 2003, Li et al. 2003). GLP1 is also which have similar bioactivities and overall metabolism, produced in neurons of the brainstem and is transported although most GLP1 secreted from the gut is C-terminally through axonal networks to diverse brain regions such amidated and 30 amino acids in length (Mojsov et al. as the cerebral cortex, hypothalamus, and thalamus http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-13-0137 Printed in Great Britain This paper is one of eight papers that form part of a thematic review section on the Molecular Evolution of GPCRs. TheDownloaded Guest Editor from for thisBioscientifica.com section was Hubert at 09/29/2021 Vaudry, 06:22:11PM European Institute for Peptides Research, University of Rouen, France. via free access Thematic Review J-L HWANG and others Evolution of GLP1 and GLP1 52:3 T16 receptor (Vrang et al. 2007, Hisadome et al. 2010). In the brain, receptor (PTHR) subfamily, iv) GCG receptor (GCGR) GLP1 is known to promote satiety by regulating appetite subfamily including GCGR, GLP1R, GLP2R, and glucose- and food intake, resulting in body weight loss (Zander dependent insulinotropic polypeptide receptor (GIPR), et al. 2002). GLP1 is also involved in neurite outgrowth and v) growth hormone-releasing hormone receptor and spatial learning ability in the central nervous system (GHRHR) subfamily including GHRHR, SCTR, vasoactive (During et al. 2003, Perry et al. 2007). intestinal peptide receptor 1 (VIPR1), VIPR2, and pituitary The physiological activities of GLP1 occur by adenylate cyclase-activating polypeptide receptor interaction with the GLP1 receptor (GLP1R), which is (ADCYAP1R1) (Harmar 2001, Fredriksson et al. 2003, expressed in pancreatic islets, brain, heart, kidney, and the Oh et al. 2006, Hwang et al. 2013). gastrointestinal tract (Graziano et al. 1993, Wei & Mojsov Although GLP1 and GLP1R are found only in 1995, Alvarez et al. 2005). Ligand-stimulated receptors vertebrates (Sherwood et al.2000, Irwin & Prentice increase intracellular cAMP by coupling to adenylate 2011), the genome history of SCTR-like GPCRs and their cyclase through the Gs protein (Drucker et al. 1987, peptide ligand genes date back to early bilaterian ancestors Fehmann et al. 1995) and by elevating cytosolic calcium (Harmar 2001, Cardoso et al. 2006). Recent advances in through activation of the Gq-mediated PLCb pathway bioinformatic tools and public genome databases for a (Wheeler et al. 1993). However, one study reports that wide range of animal kingdoms have allowed identifi- calcium responses may be secondary effects related to cation of additional members and exploration of increased intracellular cAMP (Kang et al. 2001). evolutionary history of the SCTR-like family (Cardoso GLP1R is a member of the secretin receptor (SCTR)-like et al. 2006, Nordstrom et al. 2008, Irwin & Prentice 2011, (class B1) family of G protein-coupled receptors (GPCRs) Hwang et al. 2013, Park et al. 2013). CRHR and CALCR that comprise 15 human receptors for 20 corresponding subfamilies are likely the earliest members of this family as peptide ligands (Harmar 2001, Hwang et al. 2013). As the they are present in most deuterostomes as well as in the SCTR-like receptors and their peptide ligands share similar protostomes Caenorhabditis elegans and Caenorhabditis structural features, they are likely to have emerged briggsae (nematode) and Drosophila melanogaster and through gene/genome duplications from common ances- Anopheles gambiae (arthropod) (Harmar 2001, Cardoso tors. Duplicated receptors and peptides have undergone et al. 2006). In addition, D. melanogaster contains genes sequence changes during evolution, leading to diversifica- that are phylogenetically closest to CRH and CALC out of tion of their physiological functions (Acharjee et al. 2004, all the peptide family members (Hewes & Taghert 2001, Kim et al. 2012). Specific diversification of peptides, i.e. Hwang et al. 2013). Short-range linkage analysis between Journal of Molecular Endocrinology conservation within orthologs but variation among protostome and deuterostome homologous regions that paralogs, could confer selective interaction of a peptide contain SCTR-like receptor genes demonstrated the with the cognate receptor, allowing discrimination by existence of common neighbor families for SCTR-like paralogous receptors (Wang et al. 2004, Li et al. 2005, Cho receptor genes (Cardoso et al. 2006). Recently, the et al. 2007, Lee et al. 2009). This review describes the presence of protostomian PTHR-like has been demon- influence of genome/gene/exon duplications on the strated (Mirabeau & Joly 2013). Thus, it is plausible that emergence of GLP1 and GLP1R, and the specific changes the ancestors for the CRHR (CRHR1), CALCR, and PTHR allowing selective interaction between this ligand– subfamilies have emerged during early metazoan receptor pair. evolution before the divergence of deuterostomes and protostomes. In the deuterostome lineage, besides the CRHR CALCR PTHR GCGR Evolution of SCTR-like GPCRs and their , , and gene subfamilies, the and GHRHR peptide ligands subfamily genes occurred during chordate and vertebrate evolution. The amphioxus (Branchiostoma Since the first identification of SCTR that exhibits amino floridae, a representative of the cephalochordates) genome acid sequence distinct from that of other known GPCRs contains the CRHR, CALCR,andPTHR subfamily (Ishihara et al. 1991), the SCTR-like receptors including genes, but lacks the GCGR and GHRHR subfamily genes GLP1R have been identified in a variety of invertebrate (Nordstrom et al. 2008, Hwang et al. 2013). Blast search and vertebrate species (Harmar 2001). SCTR-like GPCRs of the tunicate (Ciona intestinalis, a representative of can be categorized into the following: i) corticotropin- the urochordates) genome shows the emergence of releasing hormone receptor (CRHR) subfamily, ii) calcito- the GCGR subfamily genes together with the CRHR, nin receptor (CALCR) subfamily, iii) parathyroid hormone CALCR, and PTHR subfamily genes (Cardoso et al. 2006, http://jme.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd DOI: 10.1530/JME-13-0137 Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 06:22:11PM via free access Thematic Review J-L HWANG and others Evolution of GLP1 and GLP1 52:3 T17 receptor Hwang et al. 2013). However, no GHRHR subfamily genes pre-2R 10–13 vertebrate ancestral chromosomes (VACs