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Ion occupancy of the selectivity filter controls opening of a cytoplasmic gate in the K2P channel TALK-2

Author

Listed:
  • Lea C. Neelsen

    (Christian-Albrechts University of Kiel)

  • Elena B. Riel

    (Christian-Albrechts University of Kiel
    Weill Cornell Medical College)

  • Susanne Rinné

    (Philipps-University of Marburg)

  • Freya-Rebecca Schmid

    (Weill Cornell Medical College)

  • Björn C. Jürs

    (Christian-Albrechts University of Kiel
    University of Applied Sciences and Medical University)

  • Mauricio Bedoya

    (Universidad Católica del Maule
    Universidad Católica del Maule)

  • Jan P. Langer

    (Christian-Albrechts University of Kiel)

  • Bisher Eymsh

    (Christian-Albrechts University of Kiel)

  • Aytug K. Kiper

    (Philipps-University of Marburg)

  • Sönke Cordeiro

    (Christian-Albrechts University of Kiel)

  • Niels Decher

    (Philipps-University of Marburg)

  • Thomas Baukrowitz

    (Christian-Albrechts University of Kiel)

  • Marcus Schewe

    (Christian-Albrechts University of Kiel)

Abstract

Two-pore domain K+ (K2P) channel activity was previously thought to be controlled primarily via a selectivity filter (SF) gate. However, recent crystal structures of TASK-1 and TASK-2 revealed a lower gate at the cytoplasmic pore entrance. Here, we report functional evidence of such a lower gate in the K2P channel K2P17.1 (TALK-2, TASK-4). We identified compounds (drugs and lipids) and mutations that opened the lower gate allowing the fast modification of pore cysteine residues. Surprisingly, stimuli that directly target the SF gate (i.e., pHe., Rb+ permeation, membrane depolarization) also opened the cytoplasmic gate. Reciprocally, opening of the lower gate reduced the electric work to open the SF via voltage driven ion binding. Therefore, it appears that the SF is so rigidly locked into the TALK-2 protein structure that changes in ion occupancy can pry open a distant lower gate and, vice versa, opening of the lower gate concurrently promote SF gate opening. This concept might extent to other K+ channels that contain two gates (e.g., voltage-gated K+ channels) for which such a positive gate coupling has been suggested, but so far not directly demonstrated.

Suggested Citation

  • Lea C. Neelsen & Elena B. Riel & Susanne Rinné & Freya-Rebecca Schmid & Björn C. Jürs & Mauricio Bedoya & Jan P. Langer & Bisher Eymsh & Aytug K. Kiper & Sönke Cordeiro & Niels Decher & Thomas Baukrow, 2024. "Ion occupancy of the selectivity filter controls opening of a cytoplasmic gate in the K2P channel TALK-2," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51812-w
    DOI: 10.1038/s41467-024-51812-w
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    References listed on IDEAS

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    1. Baobin Li & Robert A. Rietmeijer & Stephen G. Brohawn, 2020. "Structural basis for pH gating of the two-pore domain K+ channel TASK2," Nature, Nature, vol. 586(7829), pages 457-462, October.
    2. Luis G. Cuello & Vishwanath Jogini & D. Marien Cortes & Albert C. Pan & Dominique G. Gagnon & Olivier Dalmas & Julio F. Cordero-Morales & Sudha Chakrapani & Benoît Roux & Eduardo Perozo, 2010. "Structural basis for the coupling between activation and inactivation gates in K+ channels," Nature, Nature, vol. 466(7303), pages 272-275, July.
    3. Wojciech Kopec & Brad S. Rothberg & Bert L. Groot, 2019. "Molecular mechanism of a potassium channel gating through activation gate-selectivity filter coupling," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
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