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J Neurosci. 2014 Jul 30;34(31):10361-78. doi: 10.1523/JNEUROSCI.0441-14.2014.

Molecular and functional diversity of GABA-A receptors in the enteric nervous system of the mouse colon.

Author information

  • 1Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, PO1 2DT, United Kingdom.
  • 2Institute 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.
  • 3Division of Neuroscience, Medical Research Institute, Dundee University, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom, and.
  • 4Laboratory of Genetic Neuropharmacology, McLean Hospital and Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts 02478.
  • 5Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, PO1 2DT, United Kingdom, jerome.swinny@port.ac.uk.

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.

Copyright © 2014 the authors 0270-6474/14/3410361-18$15.00/0.

KEYWORDS:

alprazolam; immunohistochemistry; inflammatory bowel disease; irritable bowel syndrome; stress

PMID:
25080596
[PubMed - indexed for MEDLINE]
PMCID:
PMC4115141
Free PMC Article
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