Colonic 5‐HT₄ receptors are targets for novel prokinetic drugs

Abstract

5-HT 4 receptors are G protein-coupled receptors that link to the stimulatory protein Gs which activates adenylate cyclase to increase intracellular cyclic AMP which then activates protein kinase A (PKA). 5-HT 4 receptors are expressed by neurons in the central and peripheral nervous systems especially the enteric nervous system (ENS). In general, 5-HT 4 receptors are stimulatory and their activation in the ENS enhances neurotransmitter release and propulsive motility patterns. 5-HT 4 receptors are expressed by enterochromaffin (EC) cells, Goblet cells, and most enteric neurons. The study by Konen and colleagues in this issue of Neurogastroenterology and Motility features two novel 5-HT 4 receptor agonists (5-HT 4-LA1 and 5-HT 4-LA-2) 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-HT 4-LA1 and 5-HT 4-LA2 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-HT 4 LA1 activation stimulated fecal output and increased fecal water content. These effects were detected in young and aged mice. 5-HT 4 receptors were also localized to the epithelium of the human duodenum, ileum, and colon. These studies highlight novel 5-HT 4 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-HT 4 receptors and avoiding potential unwanted side effects. K E Y W O R D S 5-HT 4 receptors, colon motility, prokinetic drugs KeyPoints • Irritable bowel syndrome-constipation (IBS-C) and chronic constipation are two common gastrointestinal motility disorders. There are no universal treatments that reliably treat constipation and that are without side effects. Howtocitethisarticle:Galligan JJ. Colonic 5-HT 4 receptors are targets for novel prokinetic drugs. Neurogastroenterology &

Reduced sodium absorption in the colon under serotonin is a potential factor aggravating secretory diarrhea

“…Thus, 5-HT reduces colonic sodium absorption. The increase in intestinal secretion caused by 5-HT is a well-known phenomenon 3,[20][21][22] and has been confirmed by electrophysiological methods, including the Ussing chamber. 23,24 Studies have reported a reduction in sodium absorption associated with serotonin.…”

Seasonal differences in intestinal flora are related to rats’ intestinal water metabolism

“…Studies have shown that 5-HT and VIP have a regulatory effect on AQPs, which may be achieved by cAMP/PKA signaling mechanisms (Kon et al, 2015;Tan et al, 2021). 5-HT activates adenylate cyclase (AC) by stimulating the protein Gs, which can increase cyclic adenosine monophosphate (cAMP), and then activate protein kinase A (PKA) (Galligan, 2021). The upregulated cAMP / PKA signaling contributes to phosphorylation and expression of AQP3, AQP4, AQP8 (Soria et al, 2009;Chen et al, 2014;Zhu, 2015).…”

Different regulatory mechanisms of Na+/ glucose transport in mouse ileum and jejunum

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