title: Differential structure of atrial and ventricular KATP: atrial KATP channels require SUR1.
abstract: The isoform-specific structure of the ATP-sensitive potassium (K(ATP)) channel endows it with differential fundamental properties, including physiological activation and pharmacology. Numerous studies have convincingly demonstrated that the pore-forming Kir6.2 (KCNJ11) and regulatory SUR2A (ABCC9) subunits are essential elements of the sarcolemmal K(ATP) channel in cardiac ventricular myocytes. Using a novel antibody directed against the COOH terminus of SUR1 (ABCC8), we show that this K(ATP) subunit is also expressed in mouse myocardium and is the dominant SUR isoform in the atrium. This suggests differential sarcolemmal K(ATP) composition in atria and ventricles, and, to test this, K(ATP) currents were measured in isolated atrial and ventricular myocytes from wild-type and SUR1(-/-) animals. K(ATP) conductance is essentially abolished in SUR1(-/-) atrial myocytes but is normal in SUR1(-/-) ventricular myocytes. Furthermore, pharmacological properties of wild-type atrial K(ATP) match closely the properties of heterologously expressed SUR1/Kir6.2 channels, whereas ventricular K(ATP) properties match those of heterologously expressed SUR2A/Kir6.2 channels. Collectively, the data demonstrate a previously unappreciated K(ATP) channel heterogeneity: SUR1 is an essential component of atrial, but not ventricular, K(ATP) channels. Differential molecular make-up of the 2 channels underlies differential pharmacology, with important implications when considering sulfonylurea therapy or dissecting the role of cardiac K(ATP) pharmacologically, as well as for understanding of the role of diazoxide in preconditioning.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Flagg
authors.forename: Harley T
authors.initials: HT
authors.lastname: Kurata
authors.forename: Ricard
authors.initials: R
authors.lastname: Masia
authors.forename: George
authors.initials: G
authors.lastname: Caputa
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.forename: William A
authors.initials: WA
authors.lastname: Coetzee
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006325:Heart Atria / Q000737:chemistry / Q000378:metabolism; D006352:Heart Ventricles / Q000737:chemistry / Q000378:metabolism; D054086:KATP Channels / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D011955:Receptors, Drug / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; C577511:Abcc9 protein, mouse; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors