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Diabetes 55:1034-1042, 2006
DOI: 10.2337/diabetes.55.04.06.db05-0788
© 2006 by the American Diabetes Association
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Blockers of the Delayed-Rectifier Potassium Current in Pancreatic ß-Cells Enhance Glucose-Dependent Insulin Secretion

James Herrington1, Yun-Ping Zhou2, Randal M. Bugianesi1, Paula M. Dulski1, Yue Feng2, Vivien A. Warren1, McHardy M. Smith1, Martin G. Kohler1, Victor M. Garsky3, Manuel Sanchez4, Michael Wagner1, Kristin Raphaelli1, Priya Banerjee1, Chinweze Ahaghotu1, Denise Wunderler1, Birgit T. Priest1, John T. Mehl5, Maria L. Garcia1, Owen B. McManus1, Gregory J. Kaczorowski1, and Robert S. Slaughter1

1 Department of Ion Channels, Merck Research Laboratories, Rahway, New Jersey
2 Department of Metabolic Disorders–Diabetes, Merck Research Laboratories, Rahway, New Jersey
3 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania
4 Department of Farmacologia, Universidad de Oviedo, Oviedo, Spain
5 Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania

Address correspondence and reprint requests to James Herrington, Merck Research Laboratories, RY80N-C31, P.O. Box 2000, Rahway, NJ 07065-0900. E-mail: james_herrington{at}merck.com

Abbreviations: GSIS, glucose-stimulated insulin secretion; GxTX, guangxitoxin; HaTX, hanatoxin; HPLC, high-performance liquid chromatography; IDR, delayed-rectifier K+ currents; KATP channel, ATP-sensitive K+ channel; KRB, Krebs-Ringer bicarbonate; TFA, trifluoroacetic acid

Delayed-rectifier K+ currents (IDR) in pancreatic ß-cells are thought to contribute to action potential repolarization and thereby modulate insulin secretion. The voltage-gated K+ channel, KV2.1, is expressed in ß-cells, and the biophysical characteristics of heterologously expressed channels are similar to those of IDR in rodent ß-cells. A novel peptidyl inhibitor of KV2.1/KV2.2 channels, guangxitoxin (GxTX)-1 (half-maximal concentration ~1 nmol/l), has been purified, characterized, and used to probe the contribution of these channels to ß-cell physiology. In mouse ß-cells, GxTX-1 inhibits 90% of IDR and, as for KV2.1, shifts the voltage dependence of channel activation to more depolarized potentials, a characteristic of gating-modifier peptides. GxTX-1 broadens the ß-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 ß-cell IDR, which may provide advantages over currently used therapies for the treatment of type 2 diabetes.


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