Glucagon-like peptide-1 receptor activation antagonizes voltage-dependent repolarizing K(+) currents in beta-cells: a possible glucose-dependent insulinotropic mechanism.
Glucagon-like peptide-1 (GLP-1) acts through its G-protein-coupled receptor to enhance glucose-stimulated insulin secretion from pancreatic beta-cells. This is believed to result from modulation of at least two ion channels: ATP-sensitive K(+) (K(ATP)) channels and voltage-dependent Ca(2+) channels. Here, we report that GLP-1 receptor signaling also regulates the activity of beta-cell voltage-dependent K(+) (K(V)) channels, themselves potent glucose-dependent regulators of insulin secretion. GLP-1 receptor activation with exendin 4 (10(-8) mol/l) in rat beta-cells antagonized K(V) currents by 43.3 +/- 6.3%, whereas the GLP-1 receptor antagonist exendin 9-39 had no effect. The effect of GLP-1 receptor activation on K(V) currents could be replicated (current reduction of 55.7 +/- 6.0%) by G-protein activation with GMP-PNP (10 nmol/l). The cAMP pathway antagonist Rp-cAMPS (100 micro mol/l) prevented current inhibition by exendin 4, implicating cAMP signaling in GLP-1 receptor modulation of beta-cell K(V) currents. Finally, exendin 4 (10(-8) mol/l) increased the amplitude (130 +/- 5.7%) and duration (285 +/- 15.9%) of the beta-cell depolarization response to current injection, independent of any effect on K(ATP) or Ca(2+) channels. The present results demonstrate that GLP-1 receptor signaling can antagonize beta-cell repolarization by reducing voltage-dependent K(+) currents, an effect likely to contribute to GLP-1's glucose-dependent insulinotropic effect.
MacDonald
Patrick E
PE
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Salapatek
Anne Marie F
AM
Wheeler
Michael B
MB
D000818:Animals; D000242:Cyclic AMP / Q000502:physiology; D004553:Electric Conductivity; D000067757:Glucagon-Like Peptide-1 Receptor; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D024642:Potassium Channels, Voltage-Gated; D018027:Receptors, Glucagon; D000242:Cyclic AMP