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.