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+ (K-ATP) 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 K-ATP channels reconstituted with mutant Kir6.2 and SUR1. We expressed a C-terminal truncated Kir6.2 (Kir6.2 Delta C26) with and without SUR1 in COS7 cells. Both Kir6.2 Delta C26 and Kir6.2 Delta C26 + SUR1 formed functional K-ATP channels. Glibenclamide inhibited Kir6.2 Delta C26 + SUR1 channels but failed to inhibit Kir6.2 Delta C26, In contrast, cibenzoline inhibited equally Kir6.2 Delta C26 and Kir6.2 Delta C26 + SUR1 channels, in a dose-dependent manner, the half-maximal concentrations of channel inhibition being 22.2 +/- 6.1 and 30.9 +/- 9.4 mu M, respectively. Furthermore, we determined also that [H-3]cibenzoline bound to Kir6.2 Delta C26. These findings confirm that cibenzoline inhibits K-ATP channels by a novel inhibitory mechanism in which cibenzoline directly affects the pore-forming Kir6.2 subunit rather than the SUR1 subunit, (C) 1998 Academic Press.