ABSTRACT
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 channels through disruption of ordered lipid domains (rafts). Super resolution imaging shows anesthetic raft disruption expels the enzyme phospholipase D2 (PLD2), activating TREK-1. Catalytically dead PLD2 robustly blocks anesthetic specific TREK-1 currents in whole cell patch-clamp. Addition of a PLD2 binding-site renders the anesthetic-insensitive TRAAK channel sensitive. General anesthetics chloroform, isoflurane, diethyl ether, xenon, and propofol all activate PLD2 in cellular membranes. Our results suggest a two-step model of anesthetic TREK-1 activation. First, inhaled anesthetics disrupt lipid rafts. Second, translocation and PLD2-dependent production of anionic lipid activates TREK-1.
