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 (IC(50), 4 nM) than for Kir6.2/SUR2A or Kir6.2/SUR2B currents (IC(50), 3 and 5 microM, 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 microM 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.
University Laboratory of Physiology, Parks Road, Oxford OX1 3PT.
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D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D012333:RNA, Messenger / Q000008:administration & dosage / Q000235:genetics; D014982:Xenopus laevis
D007211:Indoles; D054833:Isoindoles; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; C087255:mitiglinide