Localization and role of metabotropic glutamate receptors subtype 5 in the gastrointestinal tract

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.