PT  - JOURNAL ARTICLE
AU  - Mahmud Arif Pavel
AU  - E. Nicholas Petersen
AU  - Hao Wang
AU  - Richard A. Lerner
AU  - Scott B. Hansen
TI  - Studies on the mechanism of membrane mediated general anesthesia
AID  - 10.1101/313973
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 313973
4099  - http://biorxiv.org/content/early/2019/06/19/313973.short
4100  - http://biorxiv.org/content/early/2019/06/19/313973.full
AB  - 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 a hundred years 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 palmitate-mediated localization of phospholipase D2 (PLD2) to lipid rafts and subsequent production of signaling lipid phosphatidic acid (PA). Catalytically dead PLD2 robustly blocks anesthetic TREK-1 currents in cell patch-clamp. Localization of PLD2 renders the anesthetic-insensitive TRAAK channel sensitive. General anesthetics 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 anesthetic sensitivity in vivo.