The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids*

By Andrew J. Brown, S. Goldsworthy, A. A. Barnes, Michelle M Eilert, Lili Tcheang, D. Daniels, A. Muir, M. Wigglesworth, I. Kinghorn, N. Fraser and 12 more. Journal of Biological Chemistry, 2003

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GPR41 and GPR43 are related members of a homologous family of orphan G protein-coupled receptors that are tandemly encoded at a single chromosomal locus in both humans and mice. We identified the acetate anion as an agonist of human GPR43 during routine ligand bank screening in yeast. This activity was confirmed after transient transfection of GPR43 into mammalian cells using Ca2+ mobilization and [35S]guanosine 5′-O-(3-thiotriphosphate) binding assays and by coexpression with GIRK G protein-regulated potassium channels in Xenopus laevis oocytes. Other short chain carboxylic acid anions such as formate, propionate, butyrate, and pentanoate also had agonist activity. GPR41 is related to GPR43 (52% similarity; 43% identity) and was activated by similar ligands but with differing specificity for carbon chain length, with pentanoate being the most potent agonist. A third family member,GPR42, is most likely a recent gene duplication ofGPR41 and may be a pseudogene. GPR41 was expressed primarily in adipose tissue, whereas the highest levels of GPR43 were found in immune cells. The identity of the cognate physiological ligands for these receptors is not clear, although propionate is known to occur in vivo at high concentrations under certain pathophysiological conditions.

Subfields: Cellular and Molecular Neuroscience, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/df7537cf186729f0213fd7c436ca28c794c3bc61

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Citations in the corpus

Short-Chain Fatty Acids and Their Association with Signalling Pathways in Inflammation, Glucose and Lipid Metabolism (2020, background): “Presently, GPR41 and GPR43 have been identified as the most important receptors of SCFAs in the GPCR family [30,31].”
The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition (2014, background): “Both Gpr109a and Gpr43 activate Gαi proteins, and Gpr43 also signals via Gαq (28).”
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2 (2010, background): “…orphan receptors, GPR41 and GPR43, were identified by three independent research groups as receptors for short-chain fatty acids (C1-C6; Table 3) (Brown et al., 2003; Le Poul et al., 2003; Nilsson et al., 2003) and these receptors have now been renamed FFA 3 and FFA 2 , respectively (Stoddart et…”
Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-Independent Mechanisms (2012, background): “agonism on FFAR2 and FFAR3; and butyrate preferentially activates FFAR3 [3,4].”
Role of intestinal microbiota and metabolites on gut homeostasis and human diseases (2017, background): “and arthritis, have demonstrated that SCFAs could bind the GPR43 (G protein-coupled receptor 43, also known as free fatty acid receptor 2, FFAR2) and thus repressing the inflammation via interaction with FFAR2-expressing neutrophils [49, 57].”
Microbiota metabolite short chain fatty acids, GCPR, and inflammatory bowel diseases (2016, background): “GPR41 and GPR43 can be efficiently activated by acetate, propionate, butyrate and other SCFAs [39], while GPR109a can be activated SCFA SCFA IL-10 Aldh1a apoptosis proliferation IL-18 GPR43 GPR41 GPR109a Tight junction HDAC inhibition Treg T cell B cell DC neutrophil IL-10 Inflammation tumor IgA Ant”
β-Hydroxybutyrate (2017, neutral): “In fact, other endogenous short-chain fatty acids, including acetate, butyrate, and propionate, have been reported as agonists of FFAR3 (11).”
Free Fatty Acid Receptors in Health and Disease. (2020, background): “The potencies of individual SCFAs in activating FFAR2 in humans are determined by EC50 values and are ordered as C2 C3 C4 other SCFAs (39, 130, 174) (TABLE 3), whereas those for the mouse receptor are ordered as C2 C3 C4 (130).”