Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responses

J Physiol. 2010 Sep 15;588(Pt 18):3525-37. doi: 10.1113/jphysiol.2010.190207. Epub 2010 Jul 19.

Abstract

Glucose-induced β-cell action potential (AP) repolarization is regulated by potassium efflux through voltage gated (Kv) and calcium activated (K(Ca)) potassium channels. Thus, ablation of the primary Kv channel of the β-cell, Kv2.1, causes increased AP duration. However, Kv2.1(-/-) islet electrical activity still remains sensitive to the potassium channel inhibitor tetraethylammonium. Therefore, we utilized Kv2.1(-/-) islets to characterize Kv and K(Ca) channels and their respective roles in modulating the β-cell AP. The remaining Kv current present in Kv2.1(-/-) β-cells is inhibited with 5 μM CP 339818. Inhibition of the remaining Kv current in Kv2.1(-/-) mouse β-cells increased AP firing frequency by 39.6% but did not significantly enhance glucose stimulated insulin secretion (GSIS). The modest regulation of islet AP frequency by CP 339818 implicates other K(+) channels, possibly K(Ca) channels, in regulating AP repolarization. Blockade of the K(Ca) channel BK with slotoxin increased β-cell AP amplitude by 28.2%, whereas activation of BK channels with isopimaric acid decreased β-cell AP amplitude by 30.6%. Interestingly, the K(Ca) channel SK significantly contributes to Kv2.1(-/-) mouse islet AP repolarization. Inhibition of SK channels decreased AP firing frequency by 66% and increased AP duration by 67% only when Kv2.1 is ablated or inhibited and enhanced GSIS by 2.7-fold. Human islets also express SK3 channels and their β-cell AP frequency is significantly accelerated by 4.8-fold with apamin. These results uncover important repolarizing roles for both Kv and K(Ca) channels and identify distinct roles for SK channel activity in regulating calcium- versus sodium-dependent AP firing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminoquinolines
  • Animals
  • Calcium
  • Electrophysiological Phenomena / drug effects*
  • Electrophysiological Phenomena / physiology
  • Evoked Potentials / drug effects
  • Evoked Potentials / physiology
  • Glucose / pharmacology
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Imines
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Potassium Channels, Calcium-Activated / physiology*
  • Potassium Channels, Voltage-Gated / physiology*
  • Quinolines / pharmacology
  • Tolbutamide / pharmacology

Substances

  • Aminoquinolines
  • CP-339,818
  • Hypoglycemic Agents
  • Imines
  • Potassium Channels, Calcium-Activated
  • Potassium Channels, Voltage-Gated
  • Quinolines
  • Tolbutamide
  • Glucose
  • Calcium