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A mechanism for anesthetics through membrane lipids
Author(s) -
Pavel Mahmud Arif,
Petersen E. Nicholas Arif,
Lerner Richard A.,
Hansen Scott
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.797.2
Subject(s) - isoflurane , anesthetic , chemistry , pld2 , membrane , biophysics , halothane , general anesthetics , ion channel , microbiology and biotechnology , biochemistry , phospholipid , biology , medicine , receptor , anesthesia , phosphatidylcholine , organic chemistry
Since their discovery more than 150 years ago, anesthetics were speculated to target the cellular membranes. Hitherto, there is no plausible mechanism that explains how anesthetics perturbation on membrane could to lead to an effect. Here we show that the volatile anesthetics chloroform and isoflurane activate TREK‐1 channels through disruption of ordered lipid domains (rafts). Employing super resolution microscopy, we found that raft disruption by anesthetics cause the raft‐localized enzyme phospholipase D2 (PLD2) to translocate and activate TREK‐1. A catalytically dead PLD2 significantly decrease the anesthetic‐specific TREK‐1 currents. Additionally, transfer of the PLD2 binding‐site to an anesthetic‐insensitive channel, TRAAK, results in anesthetic‐sensitive currents. The general anesthetics chloroform, isoflurane, diethyl ether, xenon, and propofol were all found to activate PLD2 in cellular membranes indicating a broadly applicable mechanism. We propose a two‐step model of anesthetic TREK‐1 activation. First, inhaled anesthetics disrupt lipid rafts. Second, translocation and PLD2‐dependent production of anionic lipid activate associated channels. This model suggests anesthetics could indirectly activate ion channel in contrast to direct binding models. Support or Funding Information This work was supported by a Director's New Innovator Award (1DP2NS087943‐01 to S.B.H.) from the NIH, a graduate fellowship from the Joseph B. Scheller & Rita P. Scheller Charitable Foundation to E.N.P. We are grateful to the Iris and Junming Le Foundation for funds to purchasea super‐resolution microscope, making this study possible. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .