Reduction in voltage-gated K+ currents in primary cultured rat pancreatic beta-cells by linoleic acids

Endocrinology. 2006 Feb;147(2):674-82. doi: 10.1210/en.2005-0225. Epub 2005 Oct 27.


Free fatty acids (FFAs), in addition to glucose, have been shown to stimulate insulin release through the G protein-coupled receptor (GPCR)40 receptor in pancreatic beta-cells. Intracellular free calcium concentration ([Ca(2+)](i)) in beta-cells is elevated by FFAs, although the mechanism underlying the [Ca(2+)](i) increase is still unknown. In this study, we investigated the action of linoleic acid on voltage-gated K(+) currents. Nystatin-perforated recordings were performed on identified rat beta-cells. In the presence of nifedipine, tetrodotoxin, and tolbutamide, voltage-gated K(+) currents were observed. The transient current represents less than 5%, whereas the delayed rectifier current comprises more than 95%, of the total K(+) currents. A long-chain unsaturated FFA, linoleic acid (10 microm), reversibly decreased the amplitude of K(+) currents (to less than 10%). This reduction was abolished by the cAMP/protein kinase A system inhibitors H89 (1 microm) and Rp-cAMP (10 microm) but was not affected by protein kinase C inhibitor. In addition, forskolin and 8'-bromo-cAMP induced a similar reduction in the K(+) current as that evoked by linoleic acid. Insulin secretion and cAMP accumulation in beta-cells were also increased by linoleic acid. Methyl linoleate, which has a similar structure to linoleic acid but no binding affinity to GPR40, did not change K(+) currents. Treatment of cultured cells with GPR40-specific small interfering RNA significantly reduced the decrease in K(+) current induced by linoleic acid, whereas the cAMP-induced reduction of K(+) current was not affected. We conclude that linoleic acid reduces the voltage-gated K(+) current in rat beta-cells through GPR40 and the cAMP-protein kinase A system, leading to an increase in [Ca(2+)](i) and insulin secretion.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Linoleic Acid / metabolism*
  • Male
  • Membrane Potentials / physiology
  • Potassium Channels, Voltage-Gated / metabolism*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / physiology*


  • G-protein-coupled receptor 40, rat
  • Insulin
  • Potassium Channels, Voltage-Gated
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Linoleic Acid
  • Cyclic AMP-Dependent Protein Kinases