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.

The selective blockade of metabotropic glutamate receptor-5 attenuates fat accumulation in an <em>in vitro</em> model of benign steatosis

“…mGluR5s have been previously found in rat and mouse hepatocytes 11 , 19 and in HepG2. 7 However, considering that the mGluR5 expression on human hepatoma cells has not been extensively investigated, we decided to evaluate its expression in the hepatoma cell lines available in our laboratory (HepG2 and Huh7.5) in comparison with the receptor expression in rat cortex.…”

“…According to our results, in a mouse model of acetaminophen toxicity, the use of MPEP has been demonstrated to protect against oxidative stress. 13 However, because of its structure, MPEP may form conjugates with GSH, 19 minimizing its protective effect. On the other hand, DHPG is able to attenuate glutathione loss in oligodendrocyte precursors, thus attenuating ROS production.…”

Metabotropic Glutamate Receptor Blockade Reduces Preservation Damage in Livers from Donors after Cardiac Death

“…Metabotropic glutamate (mGlu) 5 receptor is a Group I mGlu subfamily of receptors coupled to the inositol trisphosphate/diacylglycerol pathway. Like other mGlu receptor subtypes, the mGlu5 receptor contains a phylogenetically conserved, extracellular orthosteric binding site and a more variable allosteric binding site, located on the heptahelical transmembrane domain [ 1 ]. In previous papers, we showed that the mGlu5 receptor is expressed in rat hepatocytes at comparable levels to those observed in the cerebral cortex [ 2 ].…”

Negative Modulation of the Metabotropic Glutamate Receptor Type 5 as a Potential Therapeutic Strategy in Obesity and Binge-Like Eating Behavior

“…Corroborating our findings, anti-inflammatory effects, including decrease in the expression of inflammatory cytokines, as well as in the recruitment of immune cells to the lesion site, have been also reported following negative regulation of mGluR5 in other pathological conditions, such as traumatic brain injury ( Byrnes et al, 2009 ; Yang et al, 2017 ). Considering the widespread distribution of mGluR5 (e.g., CNS, liver, hepatocytes, thymus, immune cells), further studies are necessary to address the mechanisms behind VU0490106 anti-inflammatory properties in obesity ( Boldyrev et al, 2005 ; Ferrigno et al, 2017 ).…”