Blockers of the delayed-rectifier potassium current in pancreatic β-cells enhance glucose-dependent insulin secretion

Delayed-rectifier K+ currents in pancreatic beta-cells are thought to contribute to action potential repolarization and thereby modulate insulin secretion. The voltage-gated K+ channel, Kv2.1, is expressed in beta-cells, and the biophysical characteristics of heterologously expressed channels are similar to those of I-DR in rodent beta-cells. A novel peptidyl inhibitor of K(v)2.1/K(v)2.2 channels, guangxitoxiin (GxTX)-1 (half-maximal concentration similar to 1 nmol/l), has been purified, characterized, and used to probe the contribution of these channels to beta-cell physiology. In mouse beta-cells, GxTX-1 inhibits 90% of I-DR and, as for K(v)2. 1, shifts the voltage dependence of channel activation to more depolarized potentials, a characteristic of gating-modifier peptides. GxTX-1 broadens the beta-cell action potential, enhances glucose-stimulated intracellular calcium oscillations, and enhances insulin secretion from mouse pancreatic islets in a glucose-dependent manner. These data point to a mechanism for specific enhancement of glucose-dependent insulin secretion by applying blockers of the beta-cell I-DR, which may provide advantages over currently used therapies for the treatment of type 2 diabetes.