Studies on the mechanism of general anesthesia
| Autor: | Richard A. Lerner, E. Nicholas Petersen, Hao Wang, Scott B. Hansen, Mahmud Arif Pavel |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Anesthetics are used every day in thousands of hospitals to induce loss of consciousness, yet scientists and the doctors who administer these compounds lack a molecular understanding for their action. The chemical properties of anesthetics suggest that they could target the plasma membrane. Here the authors show anesthetics directly target a subset of plasma membrane lipids to activate an ion channel in a two-step mechanism. Applying the mechanism, the authors mutate a fruit fly to be less sensitive to anesthetics and convert a nonanesthetic-sensitive channel into a sensitive one. These findings suggest a membrane-mediated mechanism will be an important consideration for other proteins of which direct binding of anesthetic has yet to explain conserved sensitivity to chemically diverse anesthetics. 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. |
| Databáze: | OpenAIRE |
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