cAMP-independent decrease of ATP-sensitive K+ channel activity by GLP-1 in rat pancreatic beta-cells

Pflugers Arch. 2000 Aug;440(4):566-72. doi: 10.1007/s004240000279.


Using the patch-clamp method, we studied the mechanism of depolarization of rat pancreatic beta-cells induced by glucagon-like peptide 1 (7-36) amide (GLP-1). GLP-1 caused depolarization in a concentration-dependent manner (0.2-100 nM). Exendin (9-39) amide, a GLP-1 receptor antagonist, prevented the GLP-1-induced depolarization. GLP-1 reduced tolbutamide-sensitive membrane currents evoked by voltage ramps from -90 to -50 mV, recorded in the perforated whole-cell configuration, suggesting that GLP-1 decreased the activity of the ATP-sensitive K+ channel (KATP). This GLP-1 effect was prevented by exendin (9-39) amide. In cells treated with Rp-cAMPS, an inhibitor of the cAMP-dependent protein kinase (PKA), GLP-1 still caused depolarization and reduced the whole-cell membrane current through KATP. Examined in the cell-attached configuration, 20 nM GLP-1, applied out of the patch, had little effect on KATP activity. In the inside-out configuration, the open time probability and the single-channel conductance of KATP in the absence of ATP inside the membrane were unaffected by the presence of 20 nM GLP-1 in the pipette. In both conditions, application of ATP to the inside of the membrane reduced KATP activity. The half-maximal concentrations (ki) of ATP were 11.6 microM without and 5.6 microM with 20 nM GLP-1 in the pipette (P<0.05). The values of the Hill coefficient (h) were 1.03 without and 1.01 with GLP-1. We conclude that GLP-1 reduces KATP activity by elevating the sensitivity of KATP to ATP, resulting in depolarization of pancreatic beta-cells. This GLP-1 action is independent of the cAMP signalling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Adenosine Triphosphate / pharmacology*
  • Animals
  • Cyclic AMP / pharmacology*
  • Electric Conductivity
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Islets of Langerhans / physiology*
  • Male
  • Membrane Potentials / drug effects
  • Peptide Fragments / pharmacology*
  • Potassium Channels / drug effects
  • Potassium Channels / physiology*
  • Protein Precursors / pharmacology*
  • Rats
  • Rats, Wistar


  • Peptide Fragments
  • Potassium Channels
  • Protein Precursors
  • Glucagon-Like Peptide 1
  • Adenosine Triphosphate
  • Glucagon
  • Cyclic AMP