Pharmaco-topology of Sulfonylurea Receptors SEPARATE DOMAINS OF THE REGULATORY SUBUNITS OFK ATP CHANNEL ISOFORMS ARE REQUIRED FOR SELECTIVE INTERACTION WITH K+ CHANNEL OPENERS

Abstract The differential responsiveness of (SUR1/KIR6.2)4 pancreatic β-cellversus (SUR2A/KIR6.2)4 sarcolemmal or (SUR2B/KIR6.0)4 smooth muscle cellK ATP channels to K+ channel openers (KCOs) is the basis for the selective prevention of hyperinsulinemia, myocardial infarction, and acute hypertension. KCO-stimulation ofK ATP channels is a unique example of functional coupling between a transport ATPase and a K+ inward rectifier. KCO binding to SUR is Mg-ATP-dependent and antagonizes the inhibition of (KIR6.0)4 pore opening by nucleotides. Patch-clamping of matched chimeric human SUR1-SUR2A/KIR6.2 channels was used to identify the SUR regions that specify the selective response of sarcolemmalversus β-cell channels to cromakalim or pinacidilversus diazoxide. The SUR2 segment containing the 12th through 17th predicted transmembrane domains, TMD12–17, confers sensitivity to the benzopyran, cromakalim, and the pyridine, pinacidil, whereas an SUR1 segment which includes TMD6–11 and the first nucleotide-binding fold, NBF1, controls responsiveness to the benzothiadiazine, diazoxide. These data are incorporated into a functional topology model for the regulatory SUR subunits ofK ATP channels.