title: KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting.
abstract: Most small-molecule inhibitors of voltage-gated ion channels display poor subtype specificity because they bind to highly conserved residues located in the channel's central cavity. Using a combined approach of scanning mutagenesis, electrophysiology, chemical ligand modification, chemical cross-linking, MS/MS-analyses and molecular modelling, we provide evidence for the binding site for adamantane derivatives and their putative access pathway in Kv7.1/KCNE1 channels. The adamantane compounds, exemplified by JNJ303, are highly potent gating modifiers that bind to fenestrations that become available when KCNE1 accessory subunits are bound to Kv7.1 channels. This mode of regulation by auxiliary subunits may facilitate the future development of potent and highly subtype-specific Kv channel inhibitors.
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster, Muenster D-48149, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wrobel
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster, Muenster D-48149, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Rothenberg
authors.affiliation: Department of Analytical Chemistry, Ruhr University of Bochum, Universitaetsstrasse 150, Bochum 44801, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Krisp
authors.affiliation: Department of Analytical Chemistry, Ruhr University of Bochum, Universitaetsstrasse 150, Bochum 44801, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Hundt
authors.affiliation: Department of Analytical Chemistry, Ruhr University of Bochum, Universitaetsstrasse 150, Bochum 44801, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fraenzel
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster, Muenster D-48149, Germany.
authors.forename: Karina
authors.initials: K
authors.lastname: Eckey
authors.affiliation: Project Management Office, Janssen Research &Development, a Division of Janssen Pharmaceutica N.V., 2340 Beerse, Belgium.
authors.forename: Joannes T M
authors.initials: JT
authors.lastname: Linders
authors.affiliation: Safety Pharmacology Research, Translational Sciences, Janssen Research &Development, a Division of Janssen Pharmaceutica N.V., 2340 Beerse, Belgium.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallacher
authors.affiliation: Safety Pharmacology Research, Translational Sciences, Janssen Research &Development, a Division of Janssen Pharmaceutica N.V., 2340 Beerse, Belgium.
authors.forename: Rob
authors.initials: R
authors.lastname: Towart
authors.affiliation: Institute of Physiology, Ruhr University of Bochum, Universitaetsstrasse 150, Bochum 44801, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Pott
authors.affiliation: Istituto di Biofisica CNR, Via De Marini 6, Genova I-16149, Italy.
authors.forename: Michael
authors.initials: M
authors.lastname: Pusch
authors.affiliation: Departments of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Departments of Medicine, Pharmacology and Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.affiliation: Department of Pharmacology, University of Alberta, 9-70 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2R3.
authors.forename: Harley T
authors.initials: HT
authors.lastname: Kurata
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster, Muenster D-48149, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster, Muenster D-48149, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Strutz-Seebohm
authors.affiliation: Department of Analytical Chemistry, Ruhr University of Bochum, Universitaetsstrasse 150, Bochum 44801, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wolters
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster, Muenster D-48149, Germany.|Interdisciplinary Centre for Clinical Research (IZKF), Faculty of Medicine, University of Münster, Münster D-48149, Germany.
authors.forename: Guiscard
authors.initials: G
authors.lastname: Seebohm
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D003432:Cross-Linking Reagents / Q000737:chemistry; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D016296:Mutagenesis; D009154:Mutation; D009865:Oocytes; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014982:Xenopus laevis
chemical_list: D003432:Cross-Linking Reagents; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D000218:Adamantane