The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids

J Biol Chem. 2003 Mar 28;278(13):11303-11. doi: 10.1074/jbc.M211495200. Epub 2002 Dec 19.

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.

MeSH terms

  • Animals
  • Base Sequence
  • Calcium / metabolism
  • Cell Line
  • Cloning, Molecular
  • Cricetinae
  • DNA Primers
  • Fatty Acids / genetics
  • Fatty Acids / pharmacology*
  • Humans
  • In Situ Hybridization
  • Luciferases / genetics
  • Molecular Sequence Data
  • Receptors, Cell Surface / drug effects*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, G-Protein-Coupled*

Substances

  • DNA Primers
  • FFAR1 protein, human
  • Fatty Acids
  • Ffar1 protein, mouse
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Luciferases
  • Calcium

Associated data

  • GENBANK/AF539809
  • GENBANK/AF539810