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Studies on the mechanism of general anesthesia

Pavel, Mahmud Arif ; Petersen, E. Nicholas ; Wang, Hao ; Lerner, Richard A. ; Hansen, Scott B.

Proceedings of the National Academy of Sciences - PNAS, 2020-06, Vol.117 (24), p.13757-13766 [Periódico revisado por pares]

United States: National Academy of Sciences

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  • Título:
    Studies on the mechanism of general anesthesia
  • Autor: Pavel, Mahmud Arif ; Petersen, E. Nicholas ; Wang, Hao ; Lerner, Richard A. ; Hansen, Scott B.
  • Assuntos: 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
  • É parte de: Proceedings of the National Academy of Sciences - PNAS, 2020-06, Vol.117 (24), p.13757-13766
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
    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.
  • Descrição: 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.
  • Editor: United States: National Academy of Sciences
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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