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18
Date Added: Nov 15, 2020
Date Added: Nov 15, 2020
One hundred sixty years after its discovery, the molecular mechanism of general anesthesia remains a notable mystery. A very wide range of agents ranging from the element xenon to steroids can act as general anesthetics on all animals from protozoa to man, suggesting that a basic cellular mechanism is involved. In this paper, we show that volatile general anesthetics cause large changes in electron spin in Drosophila fruit flies and that the spin responses are different in anesthesia-resistant mutants. We propose that anesthetics perturb electron currents in cells and describe electronic structure calculations on anesthetic–protein interactions that are consistent with this mechanism and account for hitherto unexplained features of general anesthetic pharmacology.
14
Date Added: May 31, 2020
Date Added: May 31, 2020
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.