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

1 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 (K-ATP) 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 K-ATP channels in pancreatic beta -cells, heart and non-vascular smooth muscle, respectively. 2 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. 3 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 K-ATP 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 muM, respectively). 4 Inhibition of Kir6.2/SUR1 currents was only slowly reversible on the time scale of electrophysiological experiments. 5 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 muM mitiglinide. 6 Our results show that mitiglinide is a high-affinity drug that shows a 1000 fold greater affinity for the beta -cell type than the cardiac and smooth muscle types of K-ATP channel, when measured in excised patches.