GLP‐2 receptor expression in excitatory and inhibitory enteric neurons and its role in mouse duodenum contractility

Background Glucagon‐like peptide 2 (GLP‐2), a nutrient‐responsive hormone, exerts various actions in the gastrointestinal tract that are mediated by a G‐protein coupled receptor called GLP‐2R. A little information is available on GLP‐2R expression in enteric neurons and nothing on the interstitial cells of Cajal (ICC). Methods We investigated presence and distribution of the GLP‐2R in the mouse duodenum by immunohistochemistry and the potential motor effects of GLP‐2 on the spontaneous and neurally evoked mechanical activity. Key Results The GLP‐2R was expressed by the myenteric and submucosal neurons. Labelling was also present in nerve varicosities within the circular muscular layer and at the deep muscular plexus (DMP). No immunoreactive nerve fiber was seen within the longitudinal muscle layer. The GLP‐2R‐positive neurons were either excitatory (SP‐ and choline‐acetyltransferase‐positive) or inhibitory (vasoactive intestinal polypeptide and nNOS‐positive). The ICC, both at the myenteric plexus and at the DMP, never expressed GLP‐2R but, especially those at the DMP, were surrounded by GLP‐2R‐positive nerve varicosities co‐expressing either excitatory or inhibitory neurotransmitters. Quantitative analysis demonstrated a consistent prevalence of GLP‐2R on the excitatory pathways. In agreement, the functional results showed that the administration of GLP‐2 in vitro caused decrease of the spontaneous contractions mediated by nitric oxide release and reduction of the evoked cholinergic contractions. Conclusions & Inferences The present findings indicate that the GLP‐2R is expressed by inhibitory and excitatory neurons, the GLP‐2 inhibits the muscle contractility likely decreasing cholinergic neurotransmission and increasing nitric oxide production, and this effect is possibly mediated by the ICC‐DMP recruitment.