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Structural basis for the interference between nicorandil and sulfonylurea action
F Reimann1, F M Ashcroft, F M Gribble
1Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, U.K.
Diabetes
|September 28, 2001
Summary
Nicorandil activates cardiac and smooth muscle ATP-sensitive potassium (K(ATP)) channels, but not pancreatic beta-cell channels. This selectivity is key for its antianginal effects and potential use in diabetes cardiovascular complications.
Area of Science:
- Pharmacology
- Molecular Biology
- Cardiovascular Science
Background:
- Nicorandil is an antianginal agent with dual nitric oxide donor and ATP-sensitive potassium (K(ATP)) channel opener activity.
- K(ATP) channels are crucial in cardiovascular and pancreatic beta-cell function, sharing the Kir6.2 subunit but differing in sulfonylurea receptor (SUR) subunits (SUR1, SUR2A, SUR2B).
Purpose of the Study:
- To investigate the specific domains of K(ATP) channels involved in nicorandil's action.
- To determine nicorandil's interaction with hypoglycemic sulfonylureas targeting K(ATP) channels.
Main Methods:
- Recombinant K(ATP) channels (Kir6.2/SUR1, Kir6.2/SUR2A, Kir6.2/SUR2B) expressed in Xenopus oocytes.
- Macroscopic currents recorded from excised membrane patches to assess drug and nucleotide effects.
- Mutagenesis and chimeric studies to identify critical domains for nicorandil activity and specificity.
Main Results:
- Nicorandil selectively activated Kir6.2/SUR2A and Kir6.2/SUR2B channels, but not Kir6.2/SUR1 channels.
- Activity required intracellular nucleotides, and mutations in the Walker A lysine residue of SUR2 impaired nicorandil response.
- The COOH-terminal transmembrane helices of SUR2, particularly TM 17, conferred nicorandil specificity.
- Nicorandil's action was unaffected by gliclazide but impaired by glibenclamide and glimepiride.
Conclusions:
- Nicorandil exhibits specificity for muscle K(ATP) channels (SUR2 subtypes) over pancreatic beta-cell K(ATP) channels (SUR1 subtype).
- The COOH-terminal region of SUR2 is critical for nicorandil's selective activation.
- Nicorandil's distinct interaction profile with K(ATP) channels and sulfonylureas supports its potential therapeutic applications in cardiovascular conditions, including those associated with diabetes.