Block of K v1.7 potassium currents increases glucose-stimulated insulin secretion

Rocio K. Finol-Urdaneta, Maria S. Remedi, Walter Raasch, Stefan Becker, Robert B. Clark, Nina Strüver, Evgeny Pavlov, Colin G. Nichols, Robert J. French, Heinrich Terlau

Research output: Contribution to journalArticle

Abstract

Glucose-stimulated insulin secretion (GSIS) relies on repetitive, electrical spiking activity of the beta cell membrane. Cyclic activation of voltage-gated potassium channels (K v) generates an outward, 'delayed rectifier' potassium current, which drives the repolarizing phase of each spike and modulates insulin release. Although several K v channels are expressed in pancreatic islets, their individual contributions to GSIS remain incompletely understood. We take advantage of a naturally occurring cone-snail peptide toxin, Conkunitzin-S1 (Conk-S1), which selectively blocks K v1.7 channels to provide an intrinsically limited, finely graded control of total beta cell delayed rectifier current and hence of GSIS. Conk-S1 increases GSIS in isolated rat islets, likely by reducing K v1.7-mediated delayed rectifier currents in beta cells, which yields increases in action potential firing and cytoplasmic free calcium. In rats, Conk-S1 increases glucose-dependent insulin secretion without decreasing basal glucose. Thus, we conclude that K v1.7 contributes to the membrane-repolarizing current of beta cells during GSIS and that block of this specific component of beta cell K v current offers a potential strategy for enhancing GSIS with minimal risk of hypoglycaemia during metabolic disorders such as Type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)424-434
Number of pages11
JournalEMBO Molecular Medicine
Volume4
Issue number5
DOIs
StatePublished - May 2012

Keywords

  • Conkunitzin-S1
  • Electrical signalling
  • GSIS
  • Pancreas
  • Potassium channels

ASJC Scopus subject areas

  • Molecular Medicine

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    Finol-Urdaneta, R. K., Remedi, M. S., Raasch, W., Becker, S., Clark, R. B., Strüver, N., Pavlov, E., Nichols, C. G., French, R. J., & Terlau, H. (2012). Block of K v1.7 potassium currents increases glucose-stimulated insulin secretion. EMBO Molecular Medicine, 4(5), 424-434. https://doi.org/10.1002/emmm.201200218