Kv1.3: a potential pharmacological target for diabetes

Abstract

K(+) channels, which are ubiquitous membrane proteins, play a central role in regulating the resting membrane potential and the shape and duration of the action potential in pancreatic beta-cells. There are at least three types of K(+) channels (K(ATP), K(Ca), and Kv2.1 channels) that are involved in glucose-stimulated insulin secretion in pancreatic beta-cells, and one type (Kv1.3) that is associated with the regulation of insulin sensitivity in peripheral target tissues. This article reviews the function of Kv1.3 channels that contribute to mediating insulin action in insulin-sensitive tissues. Pharmacological strategies for targeting Kv1.3 are then discussed with a focus on a rationale for the potential therapeutic use of Kv1.3 blocker in diabetic treatment.

Figure 1

A cellular mechanism for Kv1.3-involved glucose uptake in insulin-sensitive cells. IR, insulin receptor; IRS-1, insulin receptor substrate-1; GLUT4, glucose transporter 4; TNFα, tumor necrosis factor α JNK, c-JUN terminal kinase; IL-6, interleukin-6; up and down arrows, increased and decreased activities, respectively.

Figure 2

Concentration-dependent inhibition of Kv1.3 currents expressed in CHO cells by rosiglitazone and troglitazone. Superimposed currents were elicited by applying a 200-ms depolarizing pulse from a holding potential of −80 mV to +40 mV every 30 s in the absence and presence of different concentrations of drugs. Concentration-response curves for the inhibition of Kv1.3 currents. The drug-induced inhibition were measured at the end of a 200-ms depolarizing pulse of +40 mV and were normalized to the current under control conditions. The normalized currents were fitted to the Hill equation (n=7−8). Data are expressed as means±SEM.