KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting

Eva Wrobel, Ina Rothenberg, Christoph Krisp, Franziska Hundt, Benjamin Fraenzel, Karina Eckey, Joannes T. M. Linders, David J. Gallacher, Rob Towart, Lutz Pott, Michael Pusch, Tao Yang, Dan M. Roden, Harley T. Kurata, Eric Schulze-Bahr, Nathalie Strutz-Seebohm, Dirk Wolters and Guiscard Seebohm ()
Additional contact information
Eva Wrobel: Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster
Ina Rothenberg: Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster
Christoph Krisp: Ruhr University of Bochum
Franziska Hundt: Ruhr University of Bochum
Benjamin Fraenzel: Ruhr University of Bochum
Karina Eckey: Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster
Joannes T. M. Linders: Project Management Office, Janssen Research & Development
David J. Gallacher: Safety Pharmacology Research, Translational Sciences, Janssen Research & Development
Rob Towart: Safety Pharmacology Research, Translational Sciences, Janssen Research & Development
Lutz Pott: Institute of Physiology, Ruhr University of Bochum
Michael Pusch: Istituto di Biofisica CNR
Tao Yang: Vanderbilt University School of Medicine
Dan M. Roden: Pharmacology and Biomedical Informatics, Vanderbilt University School of Medicine
Harley T. Kurata: University of Alberta
Eric Schulze-Bahr: Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster
Nathalie Strutz-Seebohm: Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster
Dirk Wolters: Ruhr University of Bochum
Guiscard Seebohm: Institute for Genetics of Heart Diseases (IfGH), University Hospital Muenster

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12795

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