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, Guiscard Seebohm*

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Citations (Scopus)
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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.

Original languageEnglish
Article number12795
Pages (from-to)1-13
Number of pages13
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 12 Oct 2016
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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    Wrobel, E., Rothenberg, I., Krisp, C., Hundt, F., Fraenzel, B., Eckey, K., ... Seebohm, G. (2016). KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting. Nature Communications, 7, 1-13. [12795]. https://doi.org/10.1038/ncomms12795