Structural basis for the interference between nicorandil and sulfonylurea action.
Nicorandil is a new antianginal agent that potentially may be used to treat the cardiovascular side effects of diabetes. It is both a nitric oxide donor and an opener of ATP-sensitive K(+) (K(ATP)) channels in muscle and thereby causes vasodilation of the coronary vasculature. The aim of this study was to investigate the domains of the K(ATP) channel involved in nicorandil activity and to determine whether nicorandil interacts with hypoglycemic sulfonylureas that target K(ATP) channels in pancreatic beta-cells. K(ATP) channels in muscle and beta-cells share a common pore-forming subunit, Kir6.2, but possess alternative sulfonylurea receptors (SURs; SUR1 in beta-cells, SUR2A in cardiac muscle, and SUR2B in smooth muscle). We expressed recombinant K(ATP) channels in Xenopus oocytes and measured the effects of drugs and nucleotides by recording macroscopic currents in excised membrane patches. Nicorandil activated Kir6.2/SUR2A and Kir6.2/SUR2B but not Kir6.2/SUR1 currents, consistent with its specificity for cardiac and smooth muscle K(ATP) channels. Drug activity depended on the presence of intracellular nucleotides and was impaired when the Walker A lysine residues were mutated in either nucleotide-binding domain of SUR2. Chimeric studies showed that the COOH-terminal group of transmembrane helices (TMs), especially TM 17, is responsible for the specificity of nicorandil for channels containing SUR2. The splice variation between SUR2A and SUR2B altered the off-rate of the nicorandil response. Finally, we showed that nicorandil activity was unaffected by gliclazide, which specifically blocks SUR1-type K(ATP) channels, but was severely impaired by glibenclamide and glimepiride, which target both SUR1 and SUR2-type K(ATP) channels.
Reimann
F
F
Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, U.K.
Ashcroft
F M
FM
Gribble
F M
FM
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D004347:Drug Interactions; D004594:Electrophysiology; D005260:Female; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000502:physiology; D020108:Nicorandil / Q000494:pharmacology*; D009865:Oocytes; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014982:Xenopus laevis
D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D013453:Sulfonylurea Compounds; D020108:Nicorandil; D000255:Adenosine Triphosphate; D006899:Mixed Function Oxygenases