Effects of mitiglinide (S 21403) on Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B types of ATP‐sensitive potassium channel

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Abstract
We have investigated the mechanism of action of the novel anti‐diabetic agent mitiglinide (S 21403) on Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B types of ATP‐sensitive potassium (KATP) channel. These possess a common pore‐forming subunit, Kir6.2, and different regulatory sulphonylurea receptor (SUR) subunits. It is believed that they correspond to native KATP channels in pancreatic β‐cells, heart and non‐vascular smooth muscle, respectively. Kir6.2 was coexpressed with SUR1, SUR2A or SUR2B in Xenopus oocytes and macroscopic currents were recorded in giant inside‐out membrane patches. Mitiglinide was added to the intracellular membrane surface. Mitiglinide inhibited Kir6.2/SUR currents at two sites: a low‐affinity site on Kir6.2 and a high‐affinity site on SUR. Low‐affinity inhibition was similar for all three types of KATP channel but high‐affinity inhibition was greater for Kir6.2/SUR1 currents (IC50, 4 nM) than for Kir6.2/SUR2A or Kir6.2/SUR2B currents (IC50, 3 and 5 μM, respectively). Inhibition of Kir6.2/SUR1 currents was only slowly reversible on the time scale of electrophysiological experiments. Kir6.2/SUR1‐S1237Y currents, which previously have been shown to lack high affinity tolbutamide inhibition, resembled Kir6.2/SUR2 currents in being unaffected by 100 nM but blocked by 10 μM mitiglinide. Our results show that mitiglinide is a high‐affinity drug that shows a 1000 fold greater affinity for the β‐cell type than the cardiac and smooth muscle types of KATP channel, when measured in excised patches. British Journal of Pharmacology (2001) 132, 1542–1548; doi:10.1038/sj.bjp.0703962