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

Abstract

؊8mol/l) in rat ␤-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 ؎

Mechanisms of action of glucagon-like peptide 1 in the pancreas

“…Inclusion of the non-hydrolyzable GTP-analogue GMP-PNP (10 nM) a G-protein activator alone (MacDonald et al, 2002; replicated the effect of Ex-4 whereas the GLP-1R antagonist exendin (9-39) (10-8M; MacDonald et al, 2002) failed to have an impact on the K v current, indicating a receptor specific effect. This effect is cAMP/PKAdependent as pre-treatment with the cAMP pathway antagonist Rp-cAMPS (100μM;MacDonald et al, 2002; or the PKA inhibitor H89 (1μM; reduced the effect of GLP-1R agonists on the K v current. GLP-1R-mediated antagonism of K v was found not to depend on Epac as inclusion of the Epac activator 8CPT-2Me-cAMP (50 μM) had no effect on the delayed-rectifying current .…”

“…Patch-clamped experiments in rat islets have shown that GLP-1 (10 nM) and Ex-4 (10 nM) can antagonize K v currents (MacDonald et al, 2002). GLP-1 and Ex-4 treatment induces a 20 mV hyperpolarizing shift in the voltage dependence of steady-state activation of K v channels.…”

Voltage-dependent K + channels in pancreatic beta cells: Role, regulation and potential as therapeutic targets

“…4), we hypothesised that the physiological secretagogue GLP-1 could regulate Kv channel function. Indeed, we have found that GLP-1 and the GLP-1 receptor agonist exendin 4 inhibit voltage-dependent outward K + currents in rat beta cells voltage-clamped in the whole-cell configuration by approximately 40% in a cAMP/PKA dependent manner and prolongs the time-course of beta-cell repolarisation following transient depolarisation by current injection [54].…”

“…It is unlikely that this channel contributes to the insulinotropic effect of TEA however, since it is insensitive to the commonly used concentrations of this compound when applied extracellularly. Kv1.4, and possibly Kv4.2 [54], therefore could contribute to the TEA-insensitive inactivating current in rat beta cells, although the small amplitude of the inactivating currents observed [52] does not seem to reflect the abundance of these channels at the protein level [52,54]. As for the TEA-sensitive A-current detected in mouse beta cells [81] and mouse insulinoma cells [3], it seems likely that this current is mediated by Kv3.4, detected in mouse beta cells by immunohistochemistry [82], since this fast-inactivating Kv channel is sensitive to TEA.…”

“…Kv2.1 has been shown, with both a dominantnegative strategy and selective antagonists, to regulate excitability, [Ca 2+ ] i dynamics and insulin secretion in insulinoma cells and rodent models [3,52,53]. Furthermore, regulation of Kv channels could contribute to the modulation of insulin secretion as evidenced by the studies showing regulation of beta-cell Kv channels by exocytotic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, insulin-stimulating incretin hormones, and products of glucose metabolism [54,55,56].…”