The potassium channel K2P2.1 shapes the morphology and function of brain endothelial cells via actin network remodeling

Stefanie Lichtenberg, Laura Vinnenberg, Falk Steffen, Isabelle Plegge, Nicholas Hanuscheck, Vera Dobelmann, Joel Gruchot, Christina B. Schroeter, Haribaskar Ramachandran, Beatrice Wasser, Derya Bachir, Christopher Nelke, Jonas Franz, Christoph Riethmüller, Stefan Tenzer, Ute Distler, Christina Francisca Vogelaar, Kristina Kusche-Vihrog, Boris V. Skryabin, Timofey S. Rozhdestvensky, Albrecht Schwab, Jean Krutmann, Andrea Rossi, Thomas Budde, Stefan Bittner, Sven G. Meuth and Tobias Ruck ()
Additional contact information
Stefanie Lichtenberg: Heinrich Heine University Düsseldorf
Laura Vinnenberg: Heinrich Heine University Düsseldorf
Falk Steffen: University Medical Center of the Johannes Gutenberg-University Mainz
Isabelle Plegge: University of Muenster
Nicholas Hanuscheck: University Medical Center of the Johannes Gutenberg-University Mainz
Vera Dobelmann: Heinrich Heine University Düsseldorf
Joel Gruchot: Heinrich Heine University Düsseldorf
Christina B. Schroeter: Heinrich Heine University Düsseldorf
Haribaskar Ramachandran: Core Unit Model Development Düsseldorf
Beatrice Wasser: University Medical Center of the Johannes Gutenberg-University Mainz
Derya Bachir: Heinrich Heine University Düsseldorf
Christopher Nelke: Heinrich Heine University Düsseldorf
Jonas Franz: University of Göttingen
Christoph Riethmüller: University of Muenster
Stefan Tenzer: University Medical Center of the Johannes-Gutenberg University Mainz
Ute Distler: University Medical Center of the Johannes-Gutenberg University Mainz
Christina Francisca Vogelaar: University Medical Center of the Johannes Gutenberg-University Mainz
Kristina Kusche-Vihrog: Partner Site Hamburg/Lübeck/Kiel
Boris V. Skryabin: University of Münster
Timofey S. Rozhdestvensky: University of Münster
Albrecht Schwab: University of Münster
Jean Krutmann: Core Unit Model Development Düsseldorf
Andrea Rossi: Core Unit Model Development Düsseldorf
Thomas Budde: University of Münster
Stefan Bittner: University Medical Center of the Johannes Gutenberg-University Mainz
Sven G. Meuth: Heinrich Heine University Düsseldorf
Tobias Ruck: Heinrich Heine University Düsseldorf

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract K2P2.1 (gene: Kcnk2), a two-pore-domain potassium channel, regulates leukocyte transmigration across the blood-brain barrier by a yet unknown mechanism. We demonstrate that Kcnk2−/− mouse brain microvascular endothelial cells (MBMECs) exhibit an altered cytoskeletal structure and surface morphology with increased formation of membrane protrusions. Cell adhesion molecules cluster on those protrusions and facilitate leukocyte adhesion and migration in vitro and in vivo. We observe downregulation of K2P2.1 and activation of actin modulating proteins (cofilin 1, Arp2/3) in inflamed wildtype MBMECs. In the mechanosensitive conformation, K2P2.1 shields the phospholipid PI(4,5)P2 from interaction with other actin regulatory proteins, especially cofilin 1. Consequently, after stimulus-related K2P2.1 downregulation and dislocation from PI(4,5)P2, actin rearrangements are induced. Thus, K2P2.1-mediated regulatory processes are essential for actin dynamics, fast, reversible, and pharmacologically targetable.

Date: 2025
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DOI: 10.1038/s41467-025-61816-9

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