Luminal 5-HT4 receptors-A successful target for prokinetic actions

The prokinetic effects of 5-HT4 receptor (5-HT4R) agonists have been utilized clinically for almost three decades to relieve symptoms of constipation. Surprisingly, the mechanism(s) of action of these compounds is still being debated. Recent studies highlight luminal 5-HT(4)Rs as an alternative and effective target for these prokinetic agents. These include the study by Shokrollahi et al (2019, Neurogastroenterol Motil, e13598) published in the current issue of Neurogastroenterology and Motility, who found that activation of mucosal 5-HT(4)Rs by intraluminal prucalopride, significantly enhanced propulsive motor patterns in rabbit colon. The authors highlight the idea that development of agonists targeting luminal 5-HT(4)Rs in the colonic mucosa might be more effective and safer in achieving prokinetic effects on intestinal motility. The purpose of this mini-review is to discuss the evidence for luminal 5-HT(4)Rs as an emerging target for prokinetic agents in facilitating propulsive motor patterns in the colon.