The Orphan G Protein-coupled Receptor GPR40 Is Activated by Medium and Long Chain Fatty Acids*

By C. Briscoe, M. Tadayyon, J. Andrews, William G. Benson, J. Chambers, Michelle M Eilert, C. Ellis, N. Elshourbagy, A. Goetz, D. T. Minnick and 11 more. Journal of Biological Chemistry, 2003

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GPR40 is a member of a subfamily of homologous G protein-coupled receptors that include GPR41 and GPR43 and that have no current function or ligand ascribed. Ligand fishing experiments in HEK293 cells expressing human GPR40 revealed that a range of saturated and unsaturated carboxylic acids with carbon chain lengths greater than six were able to induce an elevation of [Ca2+] i , measured using a fluorometric imaging plate reader. 5,8,11-Eicosatriynoic acid was the most potent fatty acid tested, with a pEC50 of 5.7. G protein coupling of GPR40 was examined in Chinese hamster ovary cells expressing the Gαq/i-responsive Gal4-Elk1 reporter system. Expression of human GPR40 led to a constitutive induction of luciferase activity, which was further increased by exposure of the cells to eicosatriynoic acid. Neither the constitutive nor ligand-mediated luciferase induction was inhibited by pertussis toxin treatment, suggesting that GPR40 was coupled to Gαq/11. Expression analysis by quantitative reverse transcription-PCR showed that GPR40 was specifically expressed in brain and pancreas, with expression in rodent pancreas being localized to insulin-producing β-cells. These data suggest that some of the physiological effects of fatty acids in pancreatic islets and brain may be mediated through a cell-surface receptor.

Subfields: Cellular and Molecular Neuroscience, Endocrinology, Diabetes and Metabolism, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7b672fe8f41c30c40b6e9ae3a499cbd1481b2804

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Citations in the corpus

Homeostasis, Inflammation, and Disease Susceptibility (2015, neutral): “Many metabolites, for example, fatty acids and ketones , can be monitored both directly by GPCRs (Briscoe et al., 2003; Oh et al., 2010) and through their flow into Controllers where they are metabolized.”
Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40 (2003, background): “Although it has been reported that FFAs activate GPR40 and that GPR40 is highly expressed in pancreatic β cell”
PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. (2005, background): “Olfactory sensory neurons express a variety of GPCRs that activate the G protein G olf , which is similar to the stimulatory G s protein.”
Regulation of energy metabolism by long-chain fatty acids. (2014, background): “LCFAs bind and activate FFAR1 (GPR40) [65,66] and FFAR4 (GPR120) [67], whereas FFAR2 (GPR43) and FFAR3 (GPR41) are activated by C2–5 short-chain fatty acids [68].”
Mammalian G proteins and their cell type specific functions. (2005, background): “These effects were not PTX sensitive, suggesting that Gq/G11-mediated intracellular Ca(2) mobilization was involved (70, 296).”
Free Fatty Acid Receptors in Health and Disease. (2020, background): “Dietary FAs, especially LCFAs and MCFAs, are mainly contained in triglycerides derived from animal fats and plant oils (209, 214), whereas SCFAs are the end products of fermentation of dietary fibers by gut microbes (69, 147, 230, 332) and Citrate cycle Acetyl-CoA Malocyl-CoA C4:0 C6:0 C8:0 C10:0 C1”
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2 (2010, background): “In 2003, it was discovered by three different research groups that the receptor GPR40 can be activated by long-and medium-chain fatty acids (C6-C22; Table 3) (Briscoe et al., 2003; Itoh et al., 2003; Kotarsky et al., 2003).”
Dietary fats and prevention of type 2 diabetes (2008, background): “While the former, in particular, may mediate effects of FAs on insulin secretion [78,79], GPR41 and GPR43 can be activated by short-chain FFA [80].”
Risk Factors Contributing to Type 2 Diabetes and Recent Advances in the Treatment and Prevention (2014, background): “GPR40 agonists: G protein-coupled receptor 40 (GPR40) is a free fatty acid (FFA) receptor and Gq-type, Gq-coupled G protein-coupled receptor which is highly expressed in pancreatic β-cells [137].”