5-hydroxytryptamine receptor 4 (5-HT4 receptor)-Free fatty acid receptor 2 (GPR43) signaling axis (5-HT4R-GPR43 axis)

The 5-HT4 receptor-GPR43-5-HT-cAMP-PKA signaling axis is a multi-component biological pathway that links gut microbial activity to host metabolic and gastrointestinal functions. This axis is initiated when short-chain fatty acids (SCFAs), such as acetate and propionate produced by the fermentation of dietary fiber, activate the G protein-coupled receptor 43 (GPR43/FFAR2) located on enterochromaffin cells (UniProt: O15552). This activation triggers the release of serotonin (5-HT), which subsequently acts on 5-HT4 receptors (5-HT4R) (UniProt: Q13637). The 5-HT4R is a Gs-coupled receptor that, upon activation, increases intracellular cyclic adenosine monophosphate (cAMP) and activates protein kinase A (PKA). This signaling cascade has been shown to stimulate the secretion of glucagon-like peptide-1 (GLP-1) from intestinal L-cells, thereby improving glucose tolerance and insulin sensitivity (PMID: 28465451). Additionally, the axis plays a vital role in regulating colonic motility, making it a significant pathway for understanding and treating metabolic diseases like type 2 diabetes and gastrointestinal disorders like chronic constipation. Pharmacological modulation of this axis typically involves 5-HT4R agonists like prucalopride or the development of GPR43-targeted compounds to enhance metabolic health.

Other names

GPR43-5-HT-5-HT4R axisSCFA-GPR43-serotonin signaling pathwayGPR43-5-HT-5-HT4R-cAMP-PKA signaling axis

Activation of GPR43 by short-chain fatty acids leads to serotonin release from enterochromaffin cells, which subsequently activates 5-HT4 receptors, increasing intracellular cAMP and PKA activity to stimulate GLP-1 secretion or intestinal transit (PMID: 28465451).