Glucagon-Like Peptide-1 Receptor Activation Antagonizes Voltage-Dependent Repolarizing K+ Currents in β-Cells
A Possible Glucose-Dependent Insulinotropic Mechanism
- 1Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- 2Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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+ (KATP) channels and voltage-dependent Ca2+ channels. Here, we report that GLP-1 receptor signaling also regulates the activity of β-cell voltage-dependent K+ (KV) 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 KV 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 KV 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 KV 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 KATP 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.
Footnotes
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Address correspondence and reprint requests to Dr. Michael B. Wheeler, University of Toronto, Department of Physiology, 1 Kings College Circle, Rm. 3352, Toronto ON, Canada, M5S 1A8. E-mail: michael.wheeler{at}utoronto.ca.
Received for publication 1 March 2002 and accepted in revised form 17 May 2002.
C-clamp, current-clamp; GLP-1, glucagon-like peptide-1; GMP-PNP, guanosine 5′-[β,γ-imido]triphosphate; GSIS, glucose-stimulated insulin secretion; KATP channel, ATP-sensitive K+ channel; KCa channel, Ca2+-sensitive K+ channel; KV channel, voltage-dependent K+ channel; NSCC, nonspecific cation channel; Rp-cAMPS, the Rp-diastereomer of adenosine-3′,5′-cyclic monophosphothioate; TEA, tetraethylammonium; VDCC, voltage-dependent Ca2+ channel.
The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.
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