Original ResearchBasic and Translational—Alimentary TractActivation of Colonic Mucosal 5-HT4 Receptors Accelerates Propulsive Motility and Inhibits Visceral Hypersensitivity
Section snippets
Materials and Methods
See Supplementary Materials and Methods section for details of immunohistochemistry protocols, strains and sources of animals used, and physiological solution recipes and reagents.
Murine mucosal 5-HT4R expression
To assess the presence and relative levels of 5-HT4R transcript throughout the GI tract, real-time quantitative RT-PCR was performed in samples from the gastric corpus, duodenum, jejunum, ileum, and proximal and distal colons of SW and BALB/cJ mice. In full-thickness preparations, 5-HT4R transcript was detected from all regions, and when normalized to the endogenous control Hprt1, significantly higher levels were found in the distal and proximal colon as compared with more proximal regions of
Discussion
This study was performed to test the hypotheses that 5-HT4Rs are expressed in the colonic mucosa, and, when activated, promote propulsive motility and attenuate visceral hypersensitivity. Our findings provide novel molecular, morphologic, and physiological evidence for 5-HT4R expression in the colonic epithelium of mouse, rat, guinea pig, and human beings. Expression of this receptor was found on serotonin-containing EC cells and mucin 2–immunoreactive goblet cells, and activation of mucosal
Acknowledgments
The authors would like to thank Dr Brigitte Lavoie for consultation during the project, and Marion France for supplying electrodes for the mouse amperometry studies. The authors also would like to thank Drs Nathaniel Heintz and Eric Schmidt of Rockefeller University for 5-HT4R(BAC)-eGFP mouse tissue samples, and Drs John McRorie and Russell Spruell of Proctor and Gamble for 5-HT4R agonists.
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Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by National Institutes of Health grants DK62267 (G.M.M.) and R21HD056197 (B.G.V.M.), and P20 RR16435 from the Centers of Biomedical Research Excellence (COBRE) Program of the National Center for Research Resources, as well as a grant from the Canadian Institutes of Health Research (K.A.S.); Sarah MacEachern is supported by the Dr. T. Chen Fong Doctoral Scholarship in Neuroscience through the Hotchkiss Brain Institute; and Keith Sharkey is an Alberta Heritage Foundation for Medical Research Medical Scientist and the Crohn's and Colitis Foundation of Canada Chair in IBD Research at the University of Calgary.