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Anatomical and histological profiling of orphan G-protein-coupled receptor expression in gastrointestinal tract of C57BL/6J mice

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Abstract

G-protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors and regulate a variety of physiological and disease processes. Although the roles of many non-odorant GPCRs have been identified in vivo, several GPCRs remain orphans (oGPCRs). The gastrointestinal (GI) tract is the largest endocrine organ and is a promising target for drug discovery. Given their close link to physiological function, the anatomical and histological expression profiles of benchmark GI-related GPCRs, such as the cholecystokinin-1 receptor and GPR120, and 106 oGPCRs were investigated in the mucosal and muscle-myenteric nerve layers in the GI tract of C57BL/6J mice by quantitative real-time polymerase chain reaction. The mRNA expression patterns of these benchmark molecules were consistent with previous in situ hybridization and immunohistochemical studies, validating the experimental protocols in this study. Of 96 oGPCRs with significant mRNA expression in the GI tract, several oGPCRs showed unique expression patterns. GPR85, GPR37, GPR37L1, brain-specific angiogenesis inhibitor (BAI) 1, BAI2, BAI3, and GPRC5B mRNAs were preferentially expressed in the muscle-myenteric nerve layer, similar to GPCRs that are expressed in both the central and enteric nerve systems and that play multiple regulatory roles throughout the gut-brain axis. In contrast, GPR112, trace amine-associated receptor (TAAR) 1, TAAR2, and GPRC5A mRNAs were preferentially expressed in the mucosal layer, suggesting their potential roles in the regulation of secretion, immunity, and epithelial homeostasis. These anatomical and histological mRNA expression profiles of oGPCRs provide useful clues about the physiological roles of oGPCRs in the GI tract.

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References

  • Bjarnadottir TK, Gloriam DE, Hellstrand SH, Kristiansson H, Fredriksson R, Schioth HB (2006) Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse. Genomics 88:263–273

    Article  PubMed  CAS  Google Scholar 

  • Bjarnadottir TK, Fredriksson R, Schioth HB (2007) The adhesion GPCRs: a unique family of G protein-coupled receptors with important roles in both central and peripheral tissues. Cell Mol Life Sci 64:2104–2119

    Article  PubMed  CAS  Google Scholar 

  • Bockaert J, Pin JP (1999) Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 18:1723–1729

    Article  PubMed  CAS  Google Scholar 

  • Burdyga G, Lartigue G de, Raybould HE, Morris R, Dimaline R, Varro A, Thompson DG, Dockray GJ (2008) Cholecystokinin regulates expression of Y2 receptors in vagal afferent neurons serving the stomach. J Neurosci 28:11583–11592

    Article  PubMed  CAS  Google Scholar 

  • Cheng YJ, Lotan R (1998) Molecular cloning and characterization of a novel retinoic acid-inducible gene that encodes a putative G protein-coupled receptor. J Biol Chem 273:35008–35015

    Article  PubMed  CAS  Google Scholar 

  • Cox HM (2007) Neuropeptide Y receptors; antisecretory control of intestinal epithelial function. Auton Neurosci 133:76–85

    Article  PubMed  CAS  Google Scholar 

  • Cummings DE, Overduin J (2007) Gastrointestinal regulation of food intake. J Clin Invest 117:13–23

    Article  PubMed  CAS  Google Scholar 

  • Drucker DJ (2007) The role of gut hormones in glucose homeostasis. J Clin Invest 117:24–32

    Article  PubMed  CAS  Google Scholar 

  • Engelstoft MS, Egerod KL, Holst B, Schwartz TW (2008) A gut feeling for obesity: 7TM sensors on enteroendocrine cells. Cell Metab 8:447–449

    Article  PubMed  CAS  Google Scholar 

  • Fredriksson R, Schioth HB (2005) The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol 67:1414–1425

    Article  PubMed  CAS  Google Scholar 

  • Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63:1256–1272

    Article  PubMed  CAS  Google Scholar 

  • Gabella G (1985) Structure of the musculature of the chicken small-intestine. Anat Embryol (Berl) 171:139–149

    Article  CAS  Google Scholar 

  • Giorgio RD, Barbara G, Furness JB, Tonini M (2007) Novel therapeutic targets for enteric nervous system disorders. Trends Pharmacol Sci 28:473–481

    Article  PubMed  CAS  Google Scholar 

  • Gross KJ, Pothoulakis C (2007) Role of neuropeptides in inflammatory bowel disease. Inflamm Bowel Dis 13:918–932

    Article  PubMed  Google Scholar 

  • Hansen MB, Witte AB (2008) The role of serotonin in intestinal luminal sensing and secretion. Acta Physiol 193:311–323

    Article  CAS  Google Scholar 

  • Higashi H, Kohyama A, Hirabayashi Y (2007) Development of the drugs for metabolic diseases such as diabetes using RAIG2 and RAIG3 G-protein-coupled sugar receptors as targets. Riken, Tokio

    Google Scholar 

  • Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G (2005) Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 11:90–94

    Article  PubMed  CAS  Google Scholar 

  • Kidd M, Modlin IM, Gustafsson BI, Drozdov I, Hauso O, Pfragner R (2008) Luminal regulation of normal and neoplastic human EC cell serotonin release is mediated by bile salts, amines, tastants, and olfactants.Am J Physiol Gastrointest Liver Physiol 295:G260–G272

    Article  PubMed  CAS  Google Scholar 

  • Kim YB, Peroni OD, Aschenbach WG, Minokoshi Y, Kotani K, Zisman A, Kahn CR, Goodyear LJ, Kahn BB (2005) Muscle-specific deletion of the Glut4 glucose transporter alters multiple regulatory steps in glycogen metabolism. Mol Cell Biol 25:9713–9723

    Article  PubMed  CAS  Google Scholar 

  • Koda S, Date Y, Murakami N, Shimbara T, Hanada T, Toshinai K, Niijima A, Furuya M, Inomata N, Osuye K, Nakazato M (2005) The role of the vagal nerve in peripheral PYY3–36-induced feeding reduction in rats. Endocrinology 146:2369–2375

    Article  PubMed  CAS  Google Scholar 

  • Koh JT, Lee ZH, Ahn KY, Kim JK, Bae CS, Kim HH, Kee HJ, Kim KK (2001) Characterization of mouse brain-specific angiogenesis inhibitor 1 (BAI1) and phytanoyl-CoA alpha-hydroxylase-associated protein 1, a novel BAI1-binding protein. Mol Brain Res 87:223–237

    Article  PubMed  CAS  Google Scholar 

  • Koh JT, Kook H, Kee HJ, Seo YW, Jeong BC, Lee JH, Kim MY, Yoon KC, Jung S, Kim KK (2004) Extracellular fragment of brain-specific angiogenesis inhibitor 1 suppresses endothelial cell proliferation by blocking alpha(v)beta(5) integrin. Exp Cell Res 294:172–184

    Article  PubMed  CAS  Google Scholar 

  • Lagerstrom MC, Schioth HB (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 7:339–357

    Article  PubMed  CAS  Google Scholar 

  • Lattin J, Zidar DA, Schroder K, Kellie S, Hume DA, Sweet MJ (2007) G-protein-coupled receptor expression, function, and signaling in macrophages. J Leukoc Biol 82:16–32

    Article  PubMed  CAS  Google Scholar 

  • Leja J, Essaghir A, Essand M, Wester K, Oberg K, Totterman TH, Lloyd R, Vasmatzis G, Demoulin JB, Giandomenico V (2009) Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas. Eur J Clin Invest 39:17

    Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method.Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  • Lomax AE, Furness JB (2000) Neurochemical classification of enteric neurons in the guinea-pig distal colon. Cell Tissue Res 302:59–72

    Article  PubMed  CAS  Google Scholar 

  • Lundstrom K (2006) Latest development in drug discovery on G protein-coupled receptors. Curr Protein Pept Sci 7:465–470

    Article  PubMed  CAS  Google Scholar 

  • Lysikov YA, Morozov IA (1990) Ultrastructure of the juxtamural mucosal layer of the small-intestine. Bull Exp Biol Med 110:1583–1587

    Article  Google Scholar 

  • Marazziti D, Mandillo S, Di Pietro C, Golini E, Matteoni R, Tocchini-Valentini GP (2007) GPR37 associates with the dopamine transporter to modulate dopamine uptake and behavioral responses to dopaminergic drugs. Proc Natl Acad Sci USA 104:9846–9851

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto M, Straub RE, Marenco S, Nicodemus KK, Matsumoto SI, Fujikawa A, Miyoshi S, Shobo M, Takahashi S, Yarimizu J, Yuri M, Hiramoto M, Morita S, Yokota H, Sasayama T, Terai K, Yoshino M, Miyake A, Callicott JH, Egan MF, Meyer-Lindenberg A, Kempf L, Honea R, Vakkalanka RK, Takasaki J, Kamohara M, Soga T, Hiyama H, Ishii H, Matsuo A, Nishimura S, Matsuoka N, Kobori M, Matsushime H, Katoh M, Furuichi K, Weinberger DR (2008) The evolutionarily conserved G protein-coupled receptor SREB2/GPR85 influences brain size, behavior, and vulnerability to schizophrenia. Proc Natl Acad Sci USA 105:6133–6138

    Article  PubMed  Google Scholar 

  • Miyamoto Y, Miyamoto M (2004) Immunohistochemical localizations of secretin, cholecystokinin, and somatostatin in the rat small intestine after acute cisplatin treatment. Exp Mol Pathol 77:238–245

    Article  PubMed  CAS  Google Scholar 

  • Moore-Morris T, Varrault A, Mangoni ME, Le Digarcher A, Negre V, Dantec C, Journot L, Nargeot J, Couette B (2009) Identification of potential pharmacological targets by analysis of the comprehensive G protein-coupled receptor repertoire in the four cardiac chambers. Mol Pharmacol 75:1108–1116

    Article  PubMed  CAS  Google Scholar 

  • Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Batkai S, Marsicano G, Lutz B, Buettner C, Kunos G (2008) Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 118:3160–3169

    Article  PubMed  CAS  Google Scholar 

  • Patterson LM, Zheng HY, Berthoud HR (2002) Vagal afferents innervating the gastrointestinal tract and CCKA-receptor immunoreactivity. Anat Rec 266:10–20

    Article  PubMed  Google Scholar 

  • Pierce KL, Lefkowitz RJ (2001) Classical and new roles of beta-arrestins in the regulation of G-protein-coupled receptors. Nat Rev Neurosci 2:727–733

    Article  PubMed  CAS  Google Scholar 

  • Qu Z-D, Thacker M, Castelucci P, Bagyanszki M, Epstein ML, Furness JB (2008) Immunohistochemical analysis of neuron types in the mouse small intestine. Cell Tissue Res 334:147–161

    Article  PubMed  CAS  Google Scholar 

  • Rayasam GV, Tulasi VK, Davis JA, Bansal VS (2007) Fatty acid receptors as new therapeutic targets for diabetes. Expert Opin Ther Targets 11:661–671

    Article  PubMed  CAS  Google Scholar 

  • Regard JB, Sato IT, Coughlin SR (2008) Anatomical profiling of G protein-coupled receptor expression. Cell 135:561–571

    Article  PubMed  CAS  Google Scholar 

  • Rettenbacher M, Reubi JC (2001) Localization and characterization of neuropeptide receptors in human colon. Naunyn Schmiedebergs Arch Pharmacol 364:291–304

    Article  PubMed  CAS  Google Scholar 

  • Robbins MJ, Charles KJ, Harrison DC, Pangalos MN (2002) Localisation of the GPRC5B receptor in the rat brain and spinal cord. Mol Brain Res 106:136–144

    Article  PubMed  CAS  Google Scholar 

  • Rozengurt N, Wu SV, Chen MC, Huang C, Sternini C, Rozengurt E (2006) Colocalization of the alpha-subunit of gustducin with PYY and GLP-1 in L cells of human colon. Am J Physiol Gastrointest Liver Physiol 291:G792–G802

    Article  PubMed  CAS  Google Scholar 

  • Sanger GJ, Lee K (2008) Hormones of the gut-brain axis as targets for the treatment of upper gastrointestinal disorders. Nat Rev Drug Discov 7:241–254

    Article  PubMed  CAS  Google Scholar 

  • Spiller R (2008) Serotonin and GI clinical disorders. Neuropharmacology 55:1072–1080

    Article  PubMed  CAS  Google Scholar 

  • Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, Branchek T, Gerald CP (2007) The trace amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav 6:628–639

    Article  PubMed  CAS  Google Scholar 

  • Yona S, Lin HH, Siu WO, Gordon S, Stacey M (2008) Adhesion-GPCRs: emerging roles for novel receptors. Trends Biochem Sci 33:491–500

    Article  PubMed  CAS  Google Scholar 

  • Zhou J, Hegsted M, McCutcheon KL, Keenan MJ, Xi XC, Raggio AM, Martin RJ (2006) Peptide YY and proglucagon mRNA expression patterns and regulation in the gut. Obesity 14:683–689

    Article  PubMed  CAS  Google Scholar 

  • Zucchi R, Chiellini G, Scanlan TS, Grandy DK (2006) Trace amine-associated receptors and their ligands. Br J Pharmacol 149:967–978

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Departments of Metabolic Disorder Research, Tsukuba Research Institute, BANYU Pharmaceutical, Okubo 3, Tsukuba, Ibaraki, 300-2611, Japan

    Junko Ito, Masahiko Ito, Hirohide Nambu, Kenichi Tanaka, Hisashi Iwaasa & Shigeru Tokita

  2. Departments of Pharmacology, Tsukuba Research Institute, BANYU Pharmaceutical, Okubo 3, Tsukuba, Ibaraki, 300-2611, Japan

    Toru Fujikawa

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  1. Junko Ito
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Correspondence to Shigeru Tokita.

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Supplementary Fig. 1

Expression profiles of oGPCRs preferentially expressed in the muscle-myenteric nerve layer of the studied GI regions (DM duodenum, UIS upper intestine, LIS lower intestine, PC proximal colon, vertical axis relative expression levels \( \left( {{2^{ - \Delta \Delta {\text{Ct}}}}} \right) \) of the respective genes, filled columns expression in the mucosal nerve layers, open columns expression in the muscle-myenteric nerve layers) (PDF 20 kb)

Supplementary Fig. 2

Expression profiles of oGPCRs preferentially expressed in the mucosal layer of the studied GI regions (DM duodenum, UIS upper intestine, LIS lower intestine, PC proximal colon, vertical axis relative expression levels \( \left( {{2^{ - \Delta \Delta {\text{Ct}}}}} \right) \) of the respective genes, filled columns expression in the mucosal nerve layers, open columns expression in the muscle-myenteric nerve layers) (PDF 17.5 kb)

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Ito, J., Ito, M., Nambu, H. et al. Anatomical and histological profiling of orphan G-protein-coupled receptor expression in gastrointestinal tract of C57BL/6J mice. Cell Tissue Res 338, 257–269 (2009). https://doi.org/10.1007/s00441-009-0859-x

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