title: Deletion of the acid-sensing ion channel ASIC3 prevents gastritis-induced acid hyperresponsiveness of the stomach-brainstem axis.
abstract: Gastric acid challenge of the rat and mouse stomach is signalled to the brainstem as revealed by expression of c-Fos. The molecular sensors relevant to the detection of gastric mucosal acidosis are not known. Since the acid-sensing ion channels ASIC2 and ASIC3 are expressed by primary afferent neurons, we examined whether knockout of the ASIC2 or ASIC3 gene modifies afferent signalling of a gastric acid insult in the normal and inflamed stomach. The stomach of conscious mice (C57BL/6) was challenged with intragastric HCl; two hours later the activation of neurons in the nucleus tractus solitarii (NTS) of the brainstem was visualized by c-Fos immunocytochemistry. Mild gastritis was induced by addition of iodoacetamide (0.1%) to the drinking water for 7 days. Exposure of the gastric mucosa to HCl (0.25M) caused a 3-fold increase in the number of c-Fos-positive neurons in the NTS. This afferent input to the NTS remained unchanged by ASIC3 knockout, whereas ASIC2 knockout augmented the c-Fos response to gastric HCl challenge by 33% (P<0.01). Pretreatment of wild-type mice with iodoacetamide induced mild gastritis, as revealed by increased myeloperoxidase activity, and enhanced the number of NTS neurons responding to gastric HCl challenge by 41% (P<0.01). This gastric acid hyperresponsiveness was absent in ASIC3 knockout mice but fully preserved in ASIC2 knockout mice. The current data indicate that ASIC3 plays a major role in the acid hyperresponsiveness associated with experimental gastritis. In contrast, ASIC2 appears to dampen acid-evoked input from the stomach to the NTS.
authors.affiliation: Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UNSA UMR 6097, Sophia Antipolis, Valbonne, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wultsch
authors.forename: Evelin
authors.initials: E
authors.lastname: Painsipp
authors.forename: Anaid
authors.initials: A
authors.lastname: Shahbazian
authors.forename: Martina
authors.initials: M
authors.lastname: Mitrovic
authors.forename: Martin
authors.initials: M
authors.lastname: Edelsbrunner
authors.forename: Michel
authors.initials: M
authors.lastname: Lazdunski
authors.forename: Rainer
authors.initials: R
authors.lastname: Waldmann
authors.forename: Peter
authors.initials: P
authors.lastname: Holzer
mesh_terms: D062565:Acid Sensing Ion Channels; D000344:Afferent Pathways / Q000503:physiopathology*; D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D005756:Gastritis / Q000139:chemically induced / Q000378:metabolism*; D017353:Gene Deletion; D006851:Hydrochloric Acid; D006967:Hypersensitivity / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013270:Stomach / Q000187:drug effects
chemical_list: C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D016760:Proto-Oncogene Proteins c-fos; D015222:Sodium Channels; D006851:Hydrochloric Acid