The antiarrhythmic agent cibenzoline inhibits KATP channels by binding to Kir6.2.
We reported previously that cibenzoline, an antiarrhythmic agent, inhibits the ATP-sensitive K+ (KATP) channels of pancreatic beta-cells through a binding site distinct from that for glibenclamide. In the present study, we have determined the locus of the action of cibenzoline on KATP channels reconstituted with mutant Kir6.2 and SUR1. We expressed a C-terminal truncated Kir6.2 (Kir6. 2DeltaC26) with and without SUR1 in COS7 cells. Both Kir6.2DeltaC26 and Kir6.2DeltaC26 + SUR1 formed functional KATP channels. Glibenclamide inhibited Kir6.2DeltaC26 + SUR1 channels but failed to inhibit Kir6.2DeltaC26. In contrast, cibenzoline inhibited equally Kir6.2DeltaC26 and Kir6.2DeltaC26 + SUR1 channels, in a dose-dependent manner, the half-maximal concentrations of channel inhibition being 22.2 +/- 6.1 and 30.9 +/- 9.4 microM, respectively. Furthermore, we determined also that [3H]cibenzoline bound to Kir6. 2DeltaC26. These findings confirm that cibenzoline inhibits KATP channels by a novel inhibitory mechanism in which cibenzoline directly affects the pore-forming Kir6.2 subunit rather than the SUR1 subunit.
Mukai
E
E
Department of Metabolism & Clinical Nutrition, Kyoto University, Kyoto, 606-8507, Japan.
Ishida
H
H
Horie
M
M
Noma
A
A
Seino
Y
Y
Takano
M
M
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019556:COS Cells; D003001:Cloning, Molecular; D005905:Glyburide / Q000494:pharmacology*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D020239:Receptor Cross-Talk; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017384:Sequence Deletion; D064233:Sulfonylurea Receptors; D014162:Transfection
D018528:ATP-Binding Cassette Transporters; D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate; D005905:Glyburide; C032151:cifenline