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In general, 5\u2010HT<jats:sub>4<\/jats:sub> receptors are stimulatory and their activation in the ENS enhances neurotransmitter release and propulsive motility patterns. 5\u2010HT<jats:sub>4<\/jats:sub> receptors are expressed by enterochromaffin (EC) cells, Goblet cells, and most enteric neurons. The study by Konen and colleagues in this issue of <jats:italic>Neurogastroenterology and Motility<\/jats:italic> features two novel 5\u2010HT<jats:sub>4<\/jats:sub> receptor agonists (5\u2010HT<jats:sub>4<\/jats:sub>\u2010LA1 and 5\u2010HT<jats:sub>4<\/jats:sub>\u2010LA\u20102) that are not absorbed from the gastrointestinal tract of mice and act locally in the colonic mucosa to stimulate propulsive motility. The authors show that 5\u2010HT<jats:sub>4<\/jats:sub>\u2010LA1 and 5\u2010HT<jats:sub>4<\/jats:sub>\u2010LA2 were not absorbed from the colon and that both drugs stimulated colonic transit when administered by gavage. Both agonists stimulated colonic glass bead expulsion, and 5\u2010HT<jats:sub>4<\/jats:sub>LA1 activation stimulated fecal output and increased fecal water content. These effects were detected in young and aged mice. 5\u2010HT<jats:sub>4<\/jats:sub> receptors were also localized to the epithelium of the human duodenum, ileum, and colon. These studies highlight novel 5\u2010HT<jats:sub>4<\/jats:sub> receptor agonists that have prokinetic actions on the GI tract. These drugs are not absorbed and act locally in the gut mucosa to stimulate propulsive motility while minimizing access to systemic 5\u2010HT<jats:sub>4<\/jats:sub> receptors and avoiding potential unwanted side effects.<\/jats:p>","DOI":"10.1111\/nmo.14125","type":"journal-article","created":{"date-parts":[[2021,3,22]],"date-time":"2021-03-22T06:11:00Z","timestamp":1616393460000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Colonic 5\u2010HT<sub>4<\/sub> receptors are targets for novel prokinetic drugs"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7882-5596","authenticated-orcid":false,"given":"James J.","family":"Galligan","sequence":"first","affiliation":[{"name":"Department of Pharmacology &amp; Toxicology and the Neuroscience Program Michigan State University East Lansing MI 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