Mechanistic insights into volatile anesthetic modulation of K2P channels

  1. Aboubacar Wague
  2. Thomas T Joseph
  3. Kellie A Woll
  4. Weiming Bu
  5. Kiran A Vaidya
  6. Natarajan V Bhanu
  7. Benjamin A Garcia
  8. Crina M Nimigean
  9. Roderic G Eckenhoff
  10. Paul M Riegelhaupt  Is a corresponding author
  1. Weill Cornell Medical College, United States
  2. University of Pennsylvania, United States

Abstract

K2P potassium channels are known to be modulated by volatile anesthetic (VA) drugs and play important roles in clinically relevant effects that accompany general anesthesia. Here, we utilize a photoaffinity analog of the VA isoflurane to identify a VA binding site in the TREK1 K2P channel. The functional importance of the identified site was validated by mutagenesis and biochemical modification. Molecular dynamics simulations of TREK1 in the presence of VA found multiple neighboring residues on TREK1 TM2, TM3 and TM4 that contribute to anesthetic binding. The identified VA binding region contains residues that play roles in the mechanisms by which heat, mechanical stretch, and pharmacological modulators alter TREK1 channel activity and overlaps with positions found to modulate TASK K2P channel VA sensitivity. Our findings define molecular contacts that mediate VA binding to TREK1 channels and suggest a mechanistic basis to explain how K2P channels are modulated by VAs.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Aboubacar Wague

    Department of Anesthesiology, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Thomas T Joseph

    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Kellie A Woll

    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Weiming Bu

    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kiran A Vaidya

    Department of Anesthesiology, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Natarajan V Bhanu

    Epigenetics Program, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Benjamin A Garcia

    Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Crina M Nimigean

    Department of Anesthesiology, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6254-4447
  9. Roderic G Eckenhoff

    Department of Anesthesiology & Critical Care, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Paul M Riegelhaupt

    Anesthesiology, Weill Cornell Medical College, New York, United States
    For correspondence
    par9082@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8593-2605

Funding

Foundation for Anesthesia Education and Research (FAER-182483-2)

  • Paul M Riegelhaupt

National Institute of General Medical Sciences (K08GM132781)

  • Paul M Riegelhaupt

National Institute of General Medical Sciences (P01GM055876)

  • Roderic G Eckenhoff

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Leon D Islas, Universidad Nacional Autónoma de México, Mexico

Publication history

  1. Received: June 9, 2020
  2. Accepted: December 19, 2020
  3. Accepted Manuscript published: December 21, 2020 (version 1)
  4. Version of Record published: January 4, 2021 (version 2)

Copyright

© 2020, Wague et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Aboubacar Wague
  2. Thomas T Joseph
  3. Kellie A Woll
  4. Weiming Bu
  5. Kiran A Vaidya
  6. Natarajan V Bhanu
  7. Benjamin A Garcia
  8. Crina M Nimigean
  9. Roderic G Eckenhoff
  10. Paul M Riegelhaupt
(2020)
Mechanistic insights into volatile anesthetic modulation of K2P channels
eLife 9:e59839.
https://doi.org/10.7554/eLife.59839
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