title: Molecular and functional diversity of GABA-A receptors in the enteric nervous system of the mouse colon.
abstract: The enteric nervous system (ENS) provides the intrinsic neural control of the gastrointestinal tract (GIT) and regulates virtually all GI functions. Altered neuronal activity within the ENS underlies various GI disorders with stress being a key contributing factor. Thus, elucidating the expression and function of the neurotransmitter systems, which determine neuronal excitability within the ENS, such as the GABA-GABAA receptor (GABAAR) system, could reveal novel therapeutic targets for such GI disorders. Molecular and functionally diverse GABAARs modulate rapid GABAergic-mediated regulation of neuronal excitability throughout the nervous system. However, the cellular and subcellular GABAAR subunit expression patterns within neurochemically defined cellular circuits of the mouse ENS, together with the functional contribution of GABAAR subtypes to GI contractility remains to be determined. Immunohistochemical analyses revealed that immunoreactivity for the GABAAR gamma (γ) 2 and alphas (α) 1, 2, 3 subunits was located on somatodendritic surfaces of neurochemically distinct myenteric plexus neurons, while being on axonal compartments of submucosal plexus neurons. In contrast, immunoreactivity for the α4-5 subunits was only detected in myenteric plexus neurons. Furthermore, α-γ2 subunit immunoreactivity was located on non-neuronal interstitial cells of Cajal. In organ bath studies, GABAAR subtype-specific ligands had contrasting effects on the force and frequency of spontaneous colonic longitudinal smooth muscle contractions. Finally, enhancement of γ2-GABAAR function with alprazolam reversed the stress-induced increase in the force of spontaneous colonic contractions. The study demonstrates the molecular and functional diversity of the GABAAR system within the mouse colon providing a framework for developing GABAAR-based therapeutics in GI disorders.
authors: Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, PO1 2DT, United Kingdom.
authors: Mohsen
authors: M
authors: Seifi
authors: Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, PO1 2DT, United Kingdom.
authors: James F
authors: JF
authors: Brown
authors: Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, PO1 2DT, United Kingdom.
authors: Jeremy
authors: J
authors: Mills
authors: Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, PO1 2DT, United Kingdom, Department of Gastroenterology, Queen Alexandra Hospital, Portsmouth, PO6 3LY, United Kingdom.
authors: Pradeep
authors: P
authors: Bhandari
authors: Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom, and.
authors: Delia
authors: D
authors: Belelli
authors: Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom, and.
authors: Jeremy J
authors: JJ
authors: Lambert
authors: Laboratory of Genetic Neuropharmacology, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts 02478.
authors: Uwe
authors: U
authors: Rudolph
authors: Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, PO1 2DT, United Kingdom, jerome.swinny@port.ac.uk.
authors: Jerome D
authors: JD
authors: Swinny
mesh_terms: D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003106:Colon / Q000033:anatomy & histology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D017615:Enteric Nervous System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013004:Somatostatin / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018682:GABA Agents; D021122:Protein Subunits; D011963:Receptors, GABA-A; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D013004:Somatostatin; D003346:Corticotropin-Releasing Hormone; D019001:Nitric Oxide Synthase; D002795:Choline O-Acetyltransferase; D019331:NG-Nitroarginine Methyl Ester
keywords: alprazolam; immunohistochemistry; inflammatory bowel disease; irritable bowel syndrome; stress