Pharmaco-topology of Sulfonylurea Receptors

Abstract

The differential responsiveness of (SUR1/K(IR)6.2)4 pancreatic β-cell versus (SUR2A/K(IR)6.2)4 sarcolemmal or (SUR2B/K(IR)6.0)4 smooth muscle cell K(ATP) channels to K+ channel openers (KCOs) is the basis for the selective prevention of hyperinsulinemia, myocardial infarction, and acute hypertension. KCO-stimulation of K(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 (K(IR)6.0)4 pore opening by nucleotides. Patch-clamping of matched chimeric human SUR1-SUR2A/K(IR)6.2 channels was used to identify the SUR regions that specify the selective response of sarcolemmal versus β-cell channels to cromakalim or pinacidil versus 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 of K(ATP) channels.