title: Role for SUR2A ED domain in allosteric coupling within the K(ATP) channel complex.
abstract: Allosteric regulation of heteromultimeric ATP-sensitive potassium (K(ATP)) channels is unique among protein systems as it implies transmission of ligand-induced structural adaptation at the regulatory SUR subunit, a member of ATP-binding cassette ABCC family, to the distinct pore-forming K+ (Kir6.x) channel module. Cooperative interaction between nucleotide binding domains (NBDs) of SUR is a prerequisite for K(ATP) channel gating, yet pathways of allosteric intersubunit communication remain uncertain. Here, we analyzed the role of the ED domain, a stretch of 15 negatively charged aspartate/glutamate amino acid residues (948-962) of the SUR2A isoform, in the regulation of cardiac K(ATP) channels. Disruption of the ED domain impeded cooperative NBDs interaction and interrupted the regulation of K(ATP) channel complexes by MgADP, potassium channel openers, and sulfonylurea drugs. Thus, the ED domain is a structural component of the allosteric pathway within the K(ATP) channel complex integrating transduction of diverse nucleotide-dependent states in the regulatory SUR subunit to the open/closed states of the K+-conducting channel pore.
authors.affiliation: Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Karger
authors.forename: Sungjo
authors.initials: S
authors.lastname: Park
authors.forename: Santiago
authors.initials: S
authors.lastname: Reyes
authors.forename: Martin
authors.initials: M
authors.lastname: Bienengraeber
authors.forename: Roy B
authors.initials: RB
authors.lastname: Dyer
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
authors.forename: Alexey E
authors.initials: AE
authors.lastname: Alekseev
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000494:Allosteric Regulation / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D015221:Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011955:Receptors, Drug / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577510:ABCC9 protein, human