Role of GPR40 in fatty acid action on the beta cell line INS-1E

Biochem Biophys Res Commun. 2005 Sep 16;335(1):97-104. doi: 10.1016/j.bbrc.2005.07.042.


GPR40 is a G protein-coupled receptor expressed preferentially in beta cells, that has been implicated in mediating free fatty acid-stimulated insulin release. GPR40 RNAi impaired the ability of palmitic acid (PA) to increase both insulin secretion and intracellular calcium ([Ca2+]i). The PA-dependent [Ca2+]i increase was attenuated by inhibitors of Galphaq, PLC, and SERCA. Thus GPR40 activates the Galphaq pathway, leading to release of Ca2+ from the ER. Yet the GPR40-dependent [Ca2+]i rise was dependent on extracellular Ca2+ and elevated glucose, and was blocked by inhibition of L-type calcium channels (LTCC) or opening of the K(ATP) channel; this suggests that GPR40 promotes Ca2+ influx through up-regulation of LTCC pre-activated by glucose and membrane depolarization. Taken together, the data indicate that GPR40 mediates the increase in [Ca2+]i and insulin secretion through the Galphaq-PLC pathway, resulting in release of Ca2+ from the ER and leading to up-regulation of Ca2+ influx via LTCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels, L-Type / metabolism
  • Cell Line
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / antagonists & inhibitors
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Glucose / metabolism
  • Glucose / pharmacology
  • Insulin / metabolism
  • Insulin Secretion
  • Ion Channel Gating / drug effects
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Palmitic Acid / metabolism*
  • Palmitic Acid / pharmacology
  • Potassium Channels / metabolism
  • RNA Interference
  • Rats
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism


  • Calcium Channels, L-Type
  • G-protein-coupled receptor 40, rat
  • Insulin
  • Potassium Channels
  • Receptors, G-Protein-Coupled
  • Palmitic Acid
  • Type C Phospholipases
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Glucose
  • Calcium