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 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.

吸入性麻醉剂是一类化学性质各异的疏水性分子，能够有效地激活TWIK相关钾离子通道（TREK-1）并可逆地诱导意识丧失。在过去的一百年中，人们推测麻醉剂的作用靶点是细胞膜，然而，尚无合理的机制能够解释膜对离子通道的影响。本研究揭示了吸入性麻醉剂（如三氯甲烷和异氟烷）通过干扰磷脂酶D2（PLD2）在脂筏中的定位以及随后信号脂磷脂酸（PA）的产生来激活TREK-1。在细胞外记录中，具有催化活性的PLD2能够有效地阻断麻醉剂诱导的TREK-1电流。PLD2的定位使TRAAK通道变得敏感，而该通道在通常情况下对麻醉剂不敏感。通用麻醉剂，如三氯甲烷、异氟烷、乙醚、氙气和丙泊酚，均能破坏脂筏并激活PLD2。在果蝇的全脑中，麻醉剂能够破坏脂筏，而PLDnull突变体果蝇对麻醉的抵抗力增强。我们的研究结果确立了吸入麻醉剂的膜介导作用靶点，并表明PA有助于在体内设定麻醉敏感性的阈值。