title: Sulfonylurea receptors regulate the channel pore in ATP-sensitive potassium channels via an intersubunit salt bridge.
abstract: ATP-sensitive potassium channels play key roles in many tissues by coupling metabolic status to membrane potential. In contrast with other potassium channels, the pore-forming Kir6 subunits must co-assemble in hetero-octameric complexes with ATP-binding cassette (ABC) family sulfonylurea receptor (SUR) subunits to facilitate cell surface expression. Binding of nucleotides and drugs to SUR regulates channel gating but how these responses are communicated within the complex has remained elusive to date. We have now identified an electrostatic interaction, forming part of a functional interface between the cytoplasmic nucleotide-binding domain-2 of SUR2 subunits and the distal C-terminus of Kir6 polypeptides that determines channel response to nucleotide, potassium channel opener and antagonist. Mutation of participating residues disrupted physical interaction and regulation of expressed channels, properties that were restored in paired charge-swap mutants. Equivalent interactions were identified in Kir6.1- and Kir6.2-containing channels suggesting a conserved mechanism of allosteric regulation.
authors.affiliation: *Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield General Hospital, Leicester LE3 9QP, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Lodwick
authors.affiliation: *Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield General Hospital, Leicester LE3 9QP, U.K.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Rainbow
authors.affiliation: *Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield General Hospital, Leicester LE3 9QP, U.K.
authors.forename: Hussein N
authors.initials: HN
authors.lastname: Rubaiy
authors.affiliation: *Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield General Hospital, Leicester LE3 9QP, U.K.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al Johi
authors.affiliation: †Department of Biochemistry, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE1 9HN, U.K.
authors.forename: Geerten W
authors.initials: GW
authors.lastname: Vuister
authors.affiliation: *Department of Cardiovascular Sciences, University of Leicester, Cardiovascular Research Centre, Glenfield General Hospital, Leicester LE3 9QP, U.K.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Norman
mesh_terms: D000494:Allosteric Regulation; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D015640:Ion Channel Gating; D054086:KATP Channels / Q000737:chemistry / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity; D064233:Sulfonylurea Receptors / Q000737:chemistry / Q000378:metabolism*; D000099161:Kcnj11 Channel
chemical_list: D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577510:ABCC9 protein, human; C092520:uK-ATP-1 potassium channel