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PreprintCited by 7Ion channel regulation and functionCardiac electrophysiology and arrhythmiasErythrocyte Function and Pathophysiology

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The novel immunosuppressant Cloxyquin activates hTRESK by allosteric modulation of the selectivity filter

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Schreiber, Julian, Derksen, Anastasia, Goerges, Gunnar, Schütte, Sven, Sörgel, Jasmin, Kiper, Aytug, Strutz-Seebohm, Nathalie, Ruck, Tobias, Meuth, Sven, Decher, Niels, Seebohm, Guiscard·2023·Communications Biology
DOI 10.21203/rs.3.rs-2384580/v1PMC PMC10354012

Preprint — published as 10.1038/s42003-023-05114-4 · Paper page

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Abstract

The TWIK-related spinal cord K+ channel (TRESK) is a K 2P channel contributing to the maintenance of membrane potentials in various cells. Recently, physiological TRESK function was identified as a key player in T-cell differentiation rendering the channel a new pharmacological target for treatment of autoimmune diseases. The channel activator cloxyquin represents a promising lead compound for the development of a new class of immunomodulators. Identification of cloxyquin binding site and characterization of the molecular mechanism causing the agonism can foster the future drug development. Here, we identified the cloxyquin binding site at the M2/M4 interface by mutational scan and analyzed the molecular mechanism of action by protein modelling as well as in silico and in vitro electrophysiology using different permeating ion species (K+ / Rb+). In combination with kinetic analyses of channel inactivation, we show that cloxyquin allosterically stabilizes the inner selectivity filter facilitating the conduction process subsequently activating hTRESK.

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Metadata

Authors
Schreiber, J., Derksen, A., Goerges, G., Schütte, S., Sörgel, J., Kiper, A., Strutz-Seebohm, N., Ruck, T., Meuth, S., Decher, N., & Seebohm, G.
Affiliations
  • University of Münster (DE)
  • University Hospital Münster (DE)
  • Philipps University of Marburg (DE)
  • Marburg University
  • University Hospital Muenster
  • Heinrich Heine University Düsseldorf (DE)
Corresponding author
Schreiber, Julian
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2023-03-07
Volume
6
Issue
1
Pages
745-745
ISSN
2399-3642 (ISSN-L)
DOI
10.21203/rs.3.rs-2384580/v1
PMC
PMC10354012
OpenAlex
W4384661609
Cited by
7
References
1
Citations by year
2026: 3 · 2025: 3 · 2024: 1
FWCI
0.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • URN:NBN Resolver for Germany & Switzerland (German National Library) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Universitäts- und Landesbibliothek Münster (cc-by)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Physiology (medical) › Erythrocyte Function and Pathophysiology
Keywords
TRESK, K2P channels, allosteric modulation, selectivity filter, channel activation, immunomodulators, autoimmune disease, T cell differentiation, channel inactivation kinetics
MeSH terms
Binding Sites, Chloroquinolinols, Membrane Potentials, Potassium Channels

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