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

Author

Listed:
  • 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
    Interdisciplinary Centre for Clinical Research (IZKF), Faculty of Medicine, University of Münster)

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.

Suggested Citation

  • 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 & Da, 2016. "KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12795
    DOI: 10.1038/ncomms12795
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