The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids.
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.
Briscoe
Celia P
CP
Department of Metabolic Diseases, GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. cpb15172@gsk.com
Tadayyon
Mohammad
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Andrews
John L
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Benson
William G
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Chambers
Jon K
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Eilert
Michelle M
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Ellis
Catherine
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Elshourbagy
Nabil A
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Goetz
Aaron S
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Minnick
Dana T
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Murdock
Paul R
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Sauls
Howard R
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Shabon
Usman
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Spinage
Lisa D
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Strum
Jay C
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Szekeres
Philip G
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Tan
Kong B
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James M
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Ignar
Diane M
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Wilson
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Muir
Alison I
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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
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