Pharmaco-topology of sulfonylurea receptors. Separate domains of the regulatory subunits of K(ATP) channel isoforms are required for selective interaction with K(+) channel openers.
The differential responsiveness of (SUR1/K(IR)6.2)(4) pancreatic beta-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 beta-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.
Babenko
A P
AP
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ababenko@bcm.tmc.edu
Gonzalez
G
G
Bryan
J
J
D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D015221:Potassium Channels / Q000737:chemistry* / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology; D017433:Protein Structure, Secondary; D011955:Receptors, Drug / Q000737:chemistry* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D064233:Sulfonylurea Receptors
C577507:ABCC8 protein, human; C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; D046911:Macromolecular Substances; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D020033:Protein Isoforms; D011955:Receptors, Drug; D011993:Recombinant Fusion Proteins; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D000251:Adenosine Triphosphatases