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© 2001 by the American Diabetes Association, Inc.
Structural Basis for the Interference Between Nicorandil and Sulfonylurea Action
1 Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, U.K.
2 University Laboratory of Physiology, Parks Road, Oxford, U.K.
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+ (KATP) channels in muscle and thereby causes vasodilation of the coronary vasculature. The aim of this study was to investigate the domains of the KATP channel involved in nicorandil activity and to determine whether nicorandil interacts with hypoglycemic sulfonylureas that target KATP channels in pancreatic ß-cells. KATP channels in muscle and ß-cells share a common pore-forming subunit, Kir6.2, but possess alternative sulfonylurea receptors (SURs; SUR1 in ß-cells, SUR2A in cardiac muscle, and SUR2B in smooth muscle). We expressed recombinant KATP 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 KATP 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 KATP channels, but was severely impaired by glibenclamide and glimepiride, which target both SUR1 and SUR2-type KATP channels.
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