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AIMS/HYPOTHESIS: The carbamoylbenzoic acid derivative repaglinide is a potent short-acting insulin secretagogue that acts by closing ATP-sensitive potassium (KATP) channels in the plasma membrane of the pancreatic beta cell. In this paper we investigated. the specificity of repaglinide for three types of cloned (KATP) channel composed of the inwardly rectifying potassium channel Kir6.2 and either the sulphonylurea receptor SUR1, SUR2A or SUR2B, corresponding to the beta cell, cardiac and either smooth muscle types of KATP channel, respectively. METHODS: The action of the drug was studied by whole-cell current recordings of KATP channels expressed either in Xenopus oocytes or mammalian cells (HEK293). We also used inside-out macropatches excised from Xenopus oocytes for detailed analysis of repaglinide action. RESULTS: The drug blocked all three types of KATP channel with similar potency, by interacting with a low-affinity site on the pore-forming subunit of the channel (Kir6.2: half-maximal inhibition 230 micromol/l) and with a high-affinity site on the regulatory subunit, the sulphonylurea receptor (SUR: half-maximal inhibition 2-8 nmol/l). There was no difference in potency between channels containing SUR1, SUR2A or SUR2B. MgADP potentiated the inhibitory effect of repaglinide on Kir6.2/SUR1 and (to a lesser extent) Kir6.2/SUR2B, but not on Kir6.2/SUR2A. CONCLUSION/INTERPRETATION: Repaglinide interacts with a site common to all three types of sulphonylurea receptor leading to inhibition of the KATP channel. The fact that MgADP potentiated this effect in the case of the beta cell, but not cardiac, type of channel could help explain why the drug shows no adverse cardiovascular side-effects in vivo.

Original publication

DOI

10.1007/s001250051684

Type

Journal article

Journal

Diabetologia

Publication Date

06/2001

Volume

44

Pages

747 - 756

Keywords

ATP-Binding Cassette Transporters, Adenosine Diphosphate, Adenosine Triphosphate, Animals, Carbamates, Cell Line, Cloning, Molecular, Drug Synergism, Electric Conductivity, Female, Humans, Islets of Langerhans, Mice, Muscle, Smooth, Myocardium, Oocytes, Piperidines, Potassium Channel Blockers, Potassium Channels, Potassium Channels, Inwardly Rectifying, Rats, Receptors, Drug, Sulfonylurea Receptors, Xenopus laevis