Effect of insulinotropic agent nateglinide on Kv and Ca2+ channels in pancreatic beta-cell

Novel insulinotropic agent nateglinide stimulates insulin via binding to su lfonylurea receptor and closing the ATP-dependent K+ (K-ATP) channels in pa ncreatic beta -cells, leading to an increase in [Ca2+](i) for exocytosis, T he voltage-dependent Ca2+ channel and the delayed rectifier K+ (Kv) channel s are also present in beta -cells and their activities determine the config uration of action potential and hence contribute to the regulation of [Ca2], and insulin secretion. This study, by using the patch-clamp method in wh ole cell configuration, comparatively characterized the direct effects of s ulfonylurea receptor ligands including nateglinide, glyburide, and repaglin ide on Kv and Ca2+ channels. Each agent inhibited Kv currents in a concentr ation-dependent manner with effective concentration range two to three orde rs higher than that for blocking K-ATP channels. A marginal stimulation of Ca2+ current was observed with all drugs, while repaglinide at concentratio n greater than 300 nM inhibited Ca2+ current. The direct effects of these a ntidiabetic agents on Kv and Ca2+ channels may act concertedly with their p rimary action on KATP channels in regulating [Ca2+], and the stimulus-secre tion coupling. (C) 2001 Elsevier Science B.V. All rights reserved.