Abstract

Delayed-rectifier K⁺ currents (I_DR) in pancreatic β-cells are thought to contribute to action potential repolarization and thereby modulate insulin secretion. The voltage-gated K⁺ channel, K_V2.1, is expressed in β-cells, and the biophysical characteristics of heterologously expressed channels are similar to those of I_DR in rodent β-cells. A novel peptidyl inhibitor of K_V2.1/K_V2.2 channels, guangxitoxin (GxTX)-1 (half-maximal concentration ∼1 nmol/l), has been purified, characterized, and used to probe the contribution of these channels to β-cell physiology. In mouse β-cells, GxTX-1 inhibits 90% of I_DR and, as for K_V2.1, shifts the voltage dependence of channel activation to more depolarized potentials, a characteristic of gating-modifier peptides. GxTX-1 broadens the β-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 β-cell I_DR, which may provide advantages over currently used therapies for the treatment of type 2 diabetes.