Action potentials and insulin secretion: new insights into the role of Kv channels

Abstract

Coordinated electrical activity allows pancreatic beta-cells to respond to secretagogues with calcium entry followed by insulin secretion. Metabolism of glucose affects multiple membrane proteins including ion channels, transporters and pumps that collaborate in a cascade of electrical activity resulting in insulin release. Glucose induces beta-cell depolarization resulting in the firing of action potentials (APs), which are the primary electrical signal of the beta-cell. They are shaped by orchestrated activation of ion channels. Here we give an overview of the voltage-gated potassium (Kv) channels of the beta-cell, which are responsible in part for the falling phase of the AP, and how their regulation affects insulin secretion. beta cells contain several Kv channels allowing dynamic integration of multiple signals on repolarization of glucose-stimulated APs. Recent studies on Kv channel regulation by cAMP and arachidonic acid and on the Kv2.1 null mouse have greatly increased our understanding of beta-cell excitation-secretion coupling.

Fig. 1

Electrical activity of a mouse islet treated with 14 mM glucose, exhibiting typical depolarizing waves topped with rapidly firing action potentials.

Fig. 2

Hannatoxin significantly reduces β-cell voltage-gated potassium (Kv)-like currents. (A) Control β-cell Kv-like currents recorded in voltage clamp with voltage steps from −80 to +80 in 10 mV increments. (B) Control β-cell Kv currents 10 min following addition of 100 nM hannatoxin (HaTx). (C) Current vs. voltage plots for β-cells recorded as in A (black bar) and B (grey bar) ± s.e.m.’s (n > 7 for each condition).

Fig. 3

Islets respond to tetraethylammonium (TEA) with increased glucose-induced action potential (AP) amplitude and duration. C57 mouse islet glucose-induced (14 mM, black bar) APs treated with 15 mM TEA (grey bar).

Fig. 4

Stromatoxin (ScTx-1) significantly affects β-cell action potentials (APs). (A) Islet APs recorded in whole cell current clamp mode from an intact β-cell treated with 14 mM glucose. (B) APs from the same islet in panel (A) 2 min post-treatment with 100 nM ScTx-1. (C) Single APs recorded in 14 mM glucose alone (pre-ScTx-1) or with 14 mM glucose and 100 nM ScTx-1 (post-ScTx-1).