Studies on the mechanism of general anesthesia

Inhaled anesthetics are a chemically diverse collection of hydrophobic molecules that robustly activate TWIK-related K⁺ channels (TREK-1) and reversibly induce loss of consciousness. For 100 y, anesthetics were speculated to target cellular membranes, yet no plausible mechanism emerged to explain a...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 117; no. 24; pp. 13757 - 13766
Main Authors Pavel, Mahmud Arif, Petersen, E. Nicholas, Wang, Hao, Lerner, Richard A., Hansen, Scott B.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 16.06.2020
SeriesFrom the Cover
Subjects
Anesthesia
Anesthetics
Biological Sciences
Cell membranes
Chloroform
Diethyl ether
Hydrophobicity
Ion channels
Isoflurane
Lipid rafts
Lipids
Localization
Phosphatidic acid
Phospholipase
Phospholipase D2
Propofol
Rafts
Xenon
phospholipase D
potassium channel
lipid raft
consciousness
substrate presentation
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Summary:Inhaled anesthetics are a chemically diverse collection of hydrophobic molecules that robustly activate TWIK-related K⁺ channels (TREK-1) and reversibly induce loss of consciousness. For 100 y, anesthetics were speculated to target cellular membranes, yet no plausible mechanism emerged to explain a membrane effect on ion channels. Here we show that inhaled anesthetics (chloroform and isoflurane) activate TREK-1 through disruption of phospholipase D2 (PLD2) localization to lipid rafts and subsequent production of signaling lipid phosphatidic acid (PA). Catalytically dead PLD2 robustly blocks anesthetic TREK-1 currents in whole-cell patch-clamp recordings. Localization of PLD2 renders the TRAAK channel sensitive, a channel that is otherwise anesthetic insensitive. General anesthetics, such as chloroform, isoflurane, diethyl ether, xenon, and propofol, disrupt lipid rafts and activate PLD2. In the whole brain of flies, anesthesia disrupts rafts and PLDnull flies resist anesthesia. Our results establish a membrane-mediated target of inhaled anesthesia and suggest PA helps set thresholds of anesthetic sensitivity in vivo.
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Contributed by Richard A. Lerner, April 15, 2020 (sent for review March 9, 2020; reviewed by Steve Brohawn and Tiago Gil Oliveira)
Reviewers: S.B., University of California Berkeley; and T.O., University of Minho.
Author contributions: M.A.P., R.A.L., and S.B.H. designed research; M.A.P., E.N.P., and H.W. performed research; M.A.P., E.N.P., H.W., and S.B.H. analyzed data; and M.A.P., R.A.L., and S.B.H. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2004259117