title: The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids.
abstract: 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 [Ca(2+)](i), measured using a fluorometric imaging plate reader. 5,8,11-Eicosatriynoic acid was the most potent fatty acid tested, with a pEC(50) of 5.7. G protein coupling of GPR40 was examined in Chinese hamster ovary cells expressing the G alpha(q/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 G alpha(q/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 beta-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.
authors.affiliation: Department of Metabolic Diseases, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. cpb15172@gsk.com
authors.forename: Celia P
authors.initials: CP
authors.lastname: Briscoe
authors.forename: Mohammad
authors.initials: M
authors.lastname: Tadayyon
authors.forename: John L
authors.initials: JL
authors.lastname: Andrews
authors.forename: William G
authors.initials: WG
authors.lastname: Benson
authors.forename: Jon K
authors.initials: JK
authors.lastname: Chambers
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Eilert
authors.forename: Catherine
authors.initials: C
authors.lastname: Ellis
authors.forename: Nabil A
authors.initials: NA
authors.lastname: Elshourbagy
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Goetz
authors.forename: Dana T
authors.initials: DT
authors.lastname: Minnick
authors.forename: Paul R
authors.initials: PR
authors.lastname: Murdock
authors.forename: Howard R
authors.initials: HR
authors.lastname: Sauls
authors.forename: Usman
authors.initials: U
authors.lastname: Shabon
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Spinage
authors.forename: Jay C
authors.initials: JC
authors.lastname: Strum
authors.forename: Philip G
authors.initials: PG
authors.lastname: Szekeres
authors.forename: Kong B
authors.initials: KB
authors.lastname: Tan
authors.forename: James M
authors.initials: JM
authors.lastname: Way
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ignar
authors.forename: Shelagh
authors.initials: S
authors.lastname: Wilson
authors.forename: Alison I
authors.initials: AI
authors.lastname: Muir
mesh_terms: D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D017931:DNA Primers; D005227:Fatty Acids / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D017403:In Situ Hybridization; D008156:Luciferases / Q000235:genetics; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled
chemical_list: D017931:DNA Primers; C473034:FFAR1 protein, human; D005227:Fatty Acids; C473036:Ffar1 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D008156:Luciferases; D002118:Calcium