Epithelial 5-HT4 Receptors as a Target for Treating Constipation and Intestinal Inflammation.

Gary M Mawe, Molly Hurd, Grant W Hennig, Brigitte Lavoie

Advances in experimental medicine and biology 2022

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Because of their importance in the regulation of gut functions, several therapeutic targets involving serotonin-related proteins have been developed or repurposed to treat motility disorders, including serotonin transporter inhibitors, tryptophan hydroxylase blockers, 5-HT3 antagonists, and 5-HT4 agonists. This chapter focuses on our discovery of 5-HT4 receptors in the epithelial cells of the colon and our efforts to evaluate the effects of stimulating these receptors. 5-HT4 receptors appear to be expressed by all epithelial cells in the mouse colon, based on expression of a reporter gene driven by the 5-HT4 receptor promoter. Application of 5-HT4 agonists to the mucosal surface causes serotonin release from enterochromaffin cells, mucus secretion from goblet cells, and chloride secretion from enterocytes. Luminal administration of 5-HT4 agonists speeds up colonic motility and suppresses distention-induced nociceptive responses. Luminal administration of 5-HT4 agonists also decreases the development of, and improves recovery from, experimental colitis. Recent studies determined that the prokinetic actions of minimally absorbable 5-HT4 agonists are just as effective as absorbable compounds. Collectively, these findings indicate that targeting epithelial receptors with non-absorbable 5-HT4 agonists could offer a safe and effective strategy for treating constipation and colitis. © 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.

Citation

Gary M Mawe, Molly Hurd, Grant W Hennig, Brigitte Lavoie. Epithelial 5-HT4 Receptors as a Target for Treating Constipation and Intestinal Inflammation. Advances in experimental medicine and biology. 2022;1383:329-334