Metabolite-sensing G protein-coupled receptors (GPR41, GPR43, GPR109A) (GPR41, GPR43, GPR109A)

GPR41 (FFAR3), GPR43 (FFAR2), and GPR109A (HCAR2) are G protein-coupled receptors that sense short-chain fatty acids (SCFAs) produced by gut bacteria during the fermentation of dietary fiber. These receptors are predominantly expressed in the gut epithelium and immune cells and mediate a broad spectrum of physiological responses, including regulation of immune responses, inflammation, and energy metabolism. Their activation triggers intracellular G protein-coupled signaling cascades, primarily through Gi/o leading to decreased cAMP (common for all three), with GPR43 also signaling via Gq/11 to raise intracellular calcium. They have emerged as important links between diet, the microbiome, and diseases such as inflammatory bowel disease, obesity, cardiovascular and neurodegenerative disorders; GPR109A is also the molecular target of the drug niacin. Because of their role in these key physiological processes, all three have become subjects of intense therapeutic interest in metabolic, inflammatory, and neoplastic disease contexts.

Other names

FFAR3Free fatty acid receptor 3FFAR2Free fatty acid receptor 2HCAR2NIACR1Hydroxycarboxylic acid receptor 2PUMA-G (murine)

GPR41 and GPR43 are activated by short-chain fatty acids, decreasing cAMP via Gi/o-coupling, with GPR43 additionally activating Gq/11-dependent pathways leading to calcium influx. GPR109A is activated by niacin and butyrate, inhibiting adenylate cyclase via Gi/o proteins to reduce cAMP, and can trigger anti-inflammatory pathways in immune cells.