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World J Gastroenterol. Jul 7, 2017; 23(25): 4500-4507
Published online Jul 7, 2017. doi: 10.3748/wjg.v23.i25.4500
Localization and role of metabotropic glutamate receptors subtype 5 in the gastrointestinal tract
Andrea Ferrigno, Clarissa Berardo, Laura G Di Pasqua, Veronica Siciliano, Plinio Richelmi, Mariapia Vairetti
Andrea Ferrigno, Clarissa Berardo, Laura G Di Pasqua, Veronica Siciliano, Plinio Richelmi, Mariapia Vairetti, Department of Internal Medicine and Therapeutics (Cellular and Molecular Pharmacology and Toxicology), University of Pavia, 27100 Pavia, Italy
Author contributions: Ferrigno A contributed to data acquisition, data interpretation, composition of the draft and approval of the final version; Berardo C, Di Pasqua LG and Siciliano V contributed to data acquisition, critical revision and approval of the final version; Richelmi P contributed to data interpretation, critical revision and approval of the final version; Vairetti M contributed to conception of the study, design of the study, data interpretation, critical revision and approval of the final version.
Supported by Italian ministry of University, Research and Instruction.
Conflict-of-interest statement: Ferrigno A, Berardo C, Di Pasqua LG, Siciliano V, Richelmi P and Vairetti M declare no conflict of interest related to this publication.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Andrea Ferrigno, PhD, Department of Internal Medicine and Therapeutics (Cellular and Molecular Pharmacology and Toxicology), University of Pavia, Via Ferrata 9A, 27100 Pavia, Italy. andrea.ferrigno@unipv.it
Telephone: +39-382-986451 Fax: +39-382-986347
Received: February 4, 2017
Peer-review started: February 5, 2017
First decision: April 26, 2017
Revised: May 3, 2017
Accepted: June 19, 2017
Article in press: June 19, 2017
Published online: July 7, 2017
Processing time: 160 Days and 11.4 Hours
Abstract

Metabotropic glutamate receptor subtype 5 (mGluR5) is a Group I mGlu subfamily of receptors coupled to the inositol trisphosphate/diacylglycerol pathway. Like other mGluR subtypes, mGluR5s contain a phylogenetically conserved, extracellular orthosteric binding site and a more variable allosteric binding site, located on the heptahelical transmembrane domain. The mGluR5 receptor has proved to be a key pharmacological target in conditions affecting the central nervous system (CNS) but its presence outside the CNS underscores its potential role in pathologies affecting peripheral organs such as the gastrointestinal (GI) tract and accessory digestive organs such as the tongue, liver and pancreas. Following identification of mGluR5s in the mouth, various studies have subsequently demonstrated its involvement in mechanical allodynia, inflammation, pain and oral cancer. mGluR5 expression has also been identified in gastroesophageal vagal pathways. Indeed, experimental and human studies have demonstrated that mGluR5 blockade reduces transient lower sphincter relaxation and reflux episodes. In the intestine, mGluR5s have been shown to be involved in the control of intestinal inflammation, visceral pain and the epithelial barrier function. In the liver, mGluR5s have a permissive role in the onset of ischemic injury in rat and mice hepatocytes. Conversely, livers from mice treated with selective negative allosteric modulators and mGluR5 knockout mice are protected against ischemic injury. Similar results have been observed in experimental models of free-radical injury and in vivo mouse models of acetaminophen intoxication. Finally, mGluR5s in the pancreas are associated with insulin secretion control. The picture is, however, far from complete as the review attempts to establish in particular as regards identifying specific targets and innovative therapeutic approaches for the treatment of GI disorders.

Keywords: Metabotropic glutamate receptor subtype 5; Esophagus; Intestine; Liver; Pancreas

Core tip: Metabotropic glutamate 5 receptors (mGluR5s) belong to Group I mGlu receptors which are coupled to the inositol trisphosphate/diacylglycerol pathway. As well as in the brain, mGluR5s and their ligands have been found in peripheral organs, including those associated with the gastrointestinal (GI) tract. We review published findings about their identification and role in the mouth, esophagus, stomach and intestine and accessory digestive organs such as the tongue, liver and pancreas. We conclude that mGluR5s are still poorly studied in the GI tract and their peripheral non-synaptic signaling, and that their therapeutic potential needs to be further investigated.