2. Academic Validation
  3. Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation

Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation

  • Biol Chem. 2023 Feb 14. doi: 10.1515/hsz-2022-0266.
Christina B Schroeter 1,  Christopher Nelke 1,  Marcus Schewe 2,  Lucas Spohler 3,  Alexander M Herrmann 1,  Thomas Müntefering 1,  Niklas Huntemann 1,  Maria Kuzikov 4 5,  Philip Gribbon 4 5,  Sarah Albrecht 3,  Stefanie Bock 1,  Petra Hundehege 3,  Lea Christine Neelsen 2,  Thomas Baukrowitz 2,  Guiscard Seebohm 6,  Bernhard Wünsch 7,  Stefan Bittner 8,  Tobias Ruck 1,  Thomas Budde 9,  Sven G Meuth 1
Affiliations

Affiliations

  • 1 Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany.
  • 2 Institute of Physiology, Christian-Albrechts University Kiel, Hermann-Rodewald-Straße 5, 24118 Kiel, Germany.
  • 3 Department of Neurology with Institute for Translational Neurology, University Hospital Münster, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany.
  • 4 Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Schnackenburgallee 114, D-22525 Hamburg, Germany.
  • 5 Fraunhofer Cluster of Excellence for Immune mediated diseases (CIMD), Theodor-Stern-Kai 7, D-60596 Frankfurt, Germany.
  • 6 IfGH-Cellular Electrophysiology, Department of Cardiology and Angiology, University Hospital of Münster, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany.
  • 7 Institute for Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
  • 8 Department of Neurology, University Medical Center Mainz, Langenbeckstraße 1, D-55131 Mainz, Germany.
  • 9 Institute of Physiology I, University of Münster, Robert-Koch-Straße 27A, D-48149 Münster, Germany.
PMID: 36774650 DOI: 10.1515/hsz-2022-0266
Abstract

Modulation of two-pore domain potassium (K2P) channels has emerged as a novel field of therapeutic strategies as they may regulate immune cell activation and metabolism, inflammatory signals, or barrier integrity. One of these ion channels is the TWIK-related Potassium Channel 1 (TREK1). In the current study, we report the identification and validation of new TREK1 activators. Firstly, we used a modified potassium ion channel assay to perform high-throughput-screening of new TREK1 activators. Dose-response studies helped to identify compounds with a high separation between effectiveness and toxicity. Inside-out patch-clamp measurements of Xenopus laevis oocytes expressing TREK1 were used for further validation of these activators regarding specificity and activity. These approaches yielded three substances, E1, B3 and A2 that robustly activate TREK1. Functionally, we demonstrated that these compounds reduce levels of adhesion molecules on primary human brain and muscle endothelial cells without affecting cell viability. Finally, we studied compound A2 via voltage-clamp recordings as this activator displayed the strongest effect on adhesion molecules. Interestingly, A2 lacked TREK1 activation in the tested neuronal cell type. Taken together, this study provides data on novel TREK1 activators that might be employed to pharmacologically modulate TREK1 activity.

Keywords

BL-1249; K2P channels; TREK1; TRESK; blood-brain barrier; electrophysiology.

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