Members of the Kv1 and Kv2 voltage-dependent K(+) channel families regulate insulin secretion

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 15; no. 8; pp. 1423 - 1435
• Main Authors: MacDonald, P E, Ha, X F, Wang, J, Smukler, S R, Sun, A M, Gaisano, H Y, Salapatek, A M, Backx, P H, Wheeler, M B
• Format: Journal Article
• Language: English
• Published: United States 01.08.2001
• Subjects: 1-Methyl-3-isobutylxanthine - pharmacology; Adenoviridae - genetics; Animals; Cell Line; Cyclic AMP-Dependent Protein Kinases - metabolism; Delayed Rectifier Potassium Channels; Electric Conductivity; Gene Deletion; Gene Expression; Genetic Vectors; Glucose - pharmacology; Glyburide - pharmacology; Green Fluorescent Proteins; Insulin - metabolism; Insulin Secretion; Insulinoma - metabolism; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Islets of Langerhans - physiology; Kv1.4 Potassium Channel; Luminescent Proteins - genetics; Pancreatic Neoplasms - metabolism; Potassium Channel Blockers; Potassium Channels - genetics; Potassium Channels - physiology; Potassium Channels, Voltage-Gated; Rats; Recombinant Proteins; RNA, Messenger - analysis; Shab Potassium Channels; Tetraethylammonium - pharmacology; Transfection
• ISSN: 0888-8809
• DOI: 10.1210/me.15.8.1423

In pancreatic beta-cells, voltage-dependent K(+) (Kv) channels are potential mediators of repolarization, closure of Ca(2+) channels, and limitation of insulin secretion. The specific Kv channels expressed in beta-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 I(DR) 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 beta-cells and that antagonism of Kv2.1 may prove to be a novel glucose-dependent therapeutic treatment for type 2 diabetes.