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Molecular Endocrinology 15 (8): 1423-1435
Copyright © 2001 by The Endocrine Society

Members of the Kv1 and Kv2 Voltage-Dependent K+ Channel Families Regulate Insulin Secretion

Patrick E. MacDonald, Xiao Fang Ha, Jing Wang, Simon R. Smukler, Anthony M. Sun, Herbert Y. Gaisano, Ann Marie F. Salapatek, Peter H. Backx and Michael B. Wheeler

Departments of Medicine (H.Y.G., P.H.B., M.B.W.) and Physiology (P.E.M., X.F.H., J.W., S.R.S., A.M.S., A.M.F.S., P.H.B., M.B.W.), University of Toronto, Toronto Ontario, Canada M5S 1A8

In pancreatic ß-cells, voltage-dependent K+ (Kv) channels are potential mediators of repolarization, closure of Ca2+ channels, and limitation of insulin secretion. The specific Kv channels expressed in ß-cells and their contribution to the delayed rectifier current and regulation of insulin secretion in these cells are unclear. High-level protein expression and mRNA transcripts for Kv1.4, 1.6, and 2.1 were detected in rat islets and insulinoma cells. Inhibition of these channels with tetraethylammonium decreased IDR by approximately 85% and enhanced glucose-stimulated insulin secretion by 2- to 4-fold. Adenovirus-mediated expression of a C-terminal truncated Kv2.1 subunit, specifically eliminating Kv2 family currents, reduced delayed rectifier currents in these cells by 60–70% and enhanced glucose-stimulated insulin secretion from rat islets by 60%. Expression of a C-terminal truncated Kv1.4 subunit, abolishing Kv1 channel family currents, reduced delayed rectifier currents by approximately 25% and enhanced glucose-stimulated insulin secretion from rat islets by 40%. This study establishes that Kv2 and 1 channel homologs mediate the majority of repolarizing delayed rectifier current in rat ß-cells and that antagonism of Kv2.1 may prove to be a novel glucose-dependent therapeutic treatment for type 2 diabetes.




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