A Transmembrane Domain of the Sulfonylurea Receptor Mediates Activation of ATP-Sensitive K+ Channels by K+Channel Openers

• Published in: Molecular pharmacology 1999-08, Vol.56 (2), p.308-315
• Main Authors: D'hahan, N, Jacquet, H, Moreau, C, Catty, P, Vivaudou, M
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette Transporters; Chromans - pharmacology; Cricetinae; Diazoxide - pharmacology; Magnesium - pharmacology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Oocytes - metabolism; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Inwardly Rectifying; Protein Engineering; Protein Isoforms - metabolism; Rats; Receptors, Drug - metabolism; Recombinant Fusion Proteins - biosynthesis; Sulfonylurea Receptors; Xenopus laevis
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.56.2.308

ATP-sensitive K + (K ATP ) channels are a complex of an ATP-binding cassette transporter, the sulfonylurea receptor (SUR), and an inward rectifier K + channel subunit, Kir6.2. The diverse pharmacological responsiveness of K ATP channels from various tissues are thought to arise from distinct SUR isoforms. Thus, when assembled with Kir6.2, the pancreatic β cell isoform SUR1 is activated by the hyperglycemic drug diazoxide but not by hypotensive drugs like cromakalim, whereas the cardiac muscle isoform SUR2A is activated by cromakalim and not by diazoxide. We exploited these differences between SUR1 and SUR2A to pursue a chimeric approach designed to identify the structural determinants of SUR involved in the pharmacological activation of K ATP channels. Wild-type and chimeric SUR were coexpressed with Kir6.2 in Xenopus oocytes, and we studied the resulting channels with the patch-clamp technique in the excised inside-out configuration. The third transmembrane domain of SUR is found to be an important determinant of the response to cromakalim, which possibly harbors at least part of its binding site. Contrary to expectations, diazoxide sensitivity could not be linked specifically to the carboxyl-terminal end (nucleotide-binding domain 2) of SUR but appeared to involve complex allosteric interactions between transmembrane and nucleotide-binding domains. In addition to providing direct evidence for the structure-function relationship governing K ATP channel activation by potassium channel-opening drugs, a family of drugs of the highest therapeutic interest, these findings delineate the determinants of ligand specificity within the modular ATP-binding cassette-transporter architecture of SUR.