Glucagon-Like Peptide-1 Receptor Activation Antagonizes Voltage-Dependent Repolarizing K⁺ Currents in β-Cells

Abstract

Glucagon-like peptide-1 (GLP-1) acts through its G-protein-coupled receptor to enhance glucose-stimulated insulin secretion from pancreatic β-cells. This is believed to result from modulation of at least two ion channels: ATP-sensitive K⁺ (K_ATP) channels and voltage-dependent Ca²⁺ channels. Here, we report that GLP-1 receptor signaling also regulates the activity of β-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 β-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 μmol/l) prevented current inhibition by exendin 4, implicating cAMP signaling in GLP-1 receptor modulation of β-cell K_V currents. Finally, exendin 4 (10⁻⁸ mol/l) increased the amplitude (130 ± 5.7%) and duration (285 ± 15.9%) of the β-cell depolarization response to current injection, independent of any effect on K_ATP or Ca²⁺ channels. The present results demonstrate that GLP-1 receptor signaling can antagonize β-cell repolarization by reducing voltage-dependent K⁺ currents, an effect likely to contribute to GLP-1’s glucose-dependent insulinotropic effect.