Mechanistic insights into volatile anesthetic modulation of K2P channels
- Weill Cornell Medical College, United States
- 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
Paul M Riegelhaupt
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
- Leon D Islas, Universidad Nacional Autónoma de México, Mexico
Version history
- Received: June 9, 2020
- Accepted: December 19, 2020
- Accepted Manuscript published: December 21, 2020 (version 1)
- 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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Mechanistic insights into volatile anesthetic modulation of K2P channels
eLife 9:e59839.
https://doi.org/10.7554/eLife.59839
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