BACKGROUND AND PURPOSE: Increasing evidence implicates metabotropic glutamate receptor mGlu(7) in the pathophysiology of stress-related disorders such as depression and anxiety. Mood disorders are frequently associated with gastrointestinal (GI) dysfunction; however, the role of mGlu(7) receptors outside the CNS is unknown. This present study investigated the expression and possible functional role of mGlu(7) receptors in the mouse colon. EXPERIMENTAL APPROACH: Expression of mGlu(7) receptor mRNA and protein was studied in mouse colon by in situ hybridization and Western blotting. Effects of the selective mGlu(7) receptor agonist AMN082 on defecation and faecal parameters were studied in an isolation-induced stress model. AMN082 effects on ion transport and neuronal intracellular signalling were examined via Ussing chambers and calcium imaging. KEY RESULTS: mGlu(7) receptor mRNA and protein were highly expressed in colon mucosa. Stress-induced faecal output was unaffected by AMN082, although faecal water content was increased. In mucosa/submucosa preparations, 100 nM and 1 microM AMN082 increased bethanechol-induced changes in short-circuit current in the Ussing chamber. This was sensitive to tetrodotoxin. Also, 100 nM AMN082 significantly increased calcium signalling in a subset of submucosal neurons. CONCLUSIONS AND IMPLICATIONS: Activating mGlu(7) receptors increased colonic secretory function in vivo and ex vivo. In a group of submucosal neurons, AMN082 strongly induced calcium signalling and the presence of submucosal nerves was required for the AMN082-dependent increase in secretion. These data suggest that targeting mGlu(7) receptors may be useful in the treatment of central components of stress disorders and also stress-associated GI dysfunction such as diarrhoea or constipation.
BACKGROUND AND PURPOSE: Increasing evidence implicates metabotropic glutamate receptor mGlu(7) in the pathophysiology of stress-related disorders such as depression and anxiety. Mood disorders are frequently associated with gastrointestinal (GI) dysfunction; however, the role of mGlu(7) receptors outside the CNS is unknown. This present study investigated the expression and possible functional role of mGlu(7) receptors in the mouse colon. EXPERIMENTAL APPROACH: Expression of mGlu(7) receptor mRNA and protein was studied in mouse colon by in situ hybridization and Western blotting. Effects of the selective mGlu(7) receptor agonist AMN082 on defecation and faecal parameters were studied in an isolation-induced stress model. AMN082 effects on ion transport and neuronal intracellular signalling were examined via Ussing chambers and calcium imaging. KEY RESULTS: mGlu(7) receptor mRNA and protein were highly expressed in colon mucosa. Stress-induced faecal output was unaffected by AMN082, although faecal water content was increased. In mucosa/submucosa preparations, 100 nM and 1 microM AMN082 increased bethanechol-induced changes in short-circuit current in the Ussing chamber. This was sensitive to tetrodotoxin. Also, 100 nM AMN082 significantly increased calcium signalling in a subset of submucosal neurons. CONCLUSIONS AND IMPLICATIONS: Activating mGlu(7) receptors increased colonic secretory function in vivo and ex vivo. In a group of submucosal neurons, AMN082 strongly induced calcium signalling and the presence of submucosal nerves was required for the AMN082-dependent increase in secretion. These data suggest that targeting mGlu(7) receptors may be useful in the treatment of central components of stress disorders and also stress-associated GI dysfunction such as diarrhoea or constipation.
Authors: M Fendt; S Schmid; D R Thakker; L H Jacobson; R Yamamoto; K Mitsukawa; R Maier; F Natt; D Hüsken; P H Kelly; K H McAllister; D Hoyer; H van der Putten; J F Cryan; P J Flor Journal: Mol Psychiatry Date: 2007-08-21 Impact factor: 15.992
Authors: Katarzyna Stachowicz; Piotr Brañski; Kinga Kłak; Herman van der Putten; John F Cryan; Peter J Flor; Pilc Andrzej Journal: Behav Pharmacol Date: 2008-09 Impact factor: 2.293
Authors: Rick A Friedman; Lut Van Laer; Matthew J Huentelman; Sonal S Sheth; Els Van Eyken; Jason J Corneveaux; Waibhav D Tembe; Rebecca F Halperin; Ashley Q Thorburn; Sofie Thys; Sarah Bonneux; Erik Fransen; Jeroen Huyghe; Ilmari Pyykkö; Cor W R J Cremers; Hannie Kremer; Ingeborg Dhooge; Dafydd Stephens; Eva Orzan; Markus Pfister; Michael Bille; Agnete Parving; Martti Sorri; Paul H Van de Heyning; Linna Makmura; Jeffrey D Ohmen; Frederick H Linthicum; Jose N Fayad; John V Pearson; David W Craig; Dietrich A Stephan; Guy Van Camp Journal: Hum Mol Genet Date: 2008-12-01 Impact factor: 6.150
Authors: Catherine Cheng; Sharon M Tennant; Kristy I Azzopardi; Vicki Bennett-Wood; Elizabeth L Hartland; Roy M Robins-Browne; Marija Tauschek Journal: Infect Immun Date: 2009-03-02 Impact factor: 3.441