The mutation Y1206S increases the affinity of the sulphonylurea receptor SUR2A for glibenclamide and enhances the effects of coexpression with Kir6.2

• Published in: British journal of pharmacology 2005-04, Vol.144 (8), p.1078-1088
• Main Authors: Stephan, Damian, Stauß, Eva, Lange, Ulf, Felsch, Holger, Löffler‐Walz, Cornelia, Hambrock, Annette, Russ, Ulrich, Quast, Ulrich
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette Transporters - biosynthesis; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Dose-Response Relationship, Drug; effect of coexpression with Kir6.x; Glyburide - metabolism; Kir6.x; Medical sciences; Mice; Mutation; mutation SUR2A(Y1206S), glibenclamide; opener P1075; Pharmacology. Drug treatments; Potassium Channels - biosynthesis; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Inwardly Rectifying - biosynthesis; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - metabolism; Protein Binding - genetics; Receptors, Drug - biosynthesis; Receptors, Drug - genetics; Receptors, Drug - metabolism; Serine - genetics; Sulfonylurea Receptors; Sulphonylurea receptor SUR2A; Tyrosine - genetics
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706142

1 ATP‐sensitive K+ channels (KATP channels) are tetradimeric complexes of inwardly rectifying K+ channels (Kir6.x) and sulphonylurea receptors (SURs). The SURs SUR2A (cardiac) and SUR2B (smooth muscle) differ only in the last 42 amino acids. In SUR2B, the mutation Y1206S, located at intracellular loop 8, increases the affinity for glibenclamide (GBC) about 10‐fold. Here, we examined whether the mutation Y1206S in SUR2A had effects similar to those in SUR2B. 2 GBC bound to SUR2A with KD=20 nM; the mutation increased affinity ∼5 ×. 3 In cells, coexpression of SUR2A with Kir6.2 increased the affinity for GBC∼3 ×; with the mutant, the increase was 9 ×. 4 The mutation did not affect the affinity of SUR2A for openers; coexpression with Kir6.2 reduced opener affinity of wild‐type and mutant SUR2A by about 2 ×. 5 The negative allosteric interaction between the opener, P1075, and GBC at wild‐type and mutant SUR2A was markedly affected by the presence of MgATP and by coexpression with Kir6.2. 6 In inside‐out patches, GBC inhibited the wild‐type Kir6.2/SUR2A and 2B channels with IC50 values of 27 nM; the mutation shifted the IC50 values to ∼1 nM. 7 The data show that the mutation Y1206S increased the affinity of SUR2A for GBC and modulated the effects of coexpression. Overall, the changes were similar to those observed with SUR2B(Y1206S), suggesting that the differences in the last 42 carboxy‐terminal amino acids of SUR2A and 2B are of limited influence on the binding of GBC and P1075 to the SUR2 isoforms. British Journal of Pharmacology (2005) 144, 1078–1088. doi:10.1038/sj.bjp.0706142