The K2P channels are highly conserved from C. elegans to humans with 15 genes identified. They are structurally distinct from other K channel family members, with four transmembrane segments and 2P domains in tandem. K2P channels are homo- or hetero-dimers . The 15 human K2P channels are classified into 6 distinct structural and functional subfamilies named TWIK-, THIK-, TREK-, TASK-, TALK- and TRESK-. K2P channels are expected to play a dominant role in cell electrogenesis, controlling the resting membrane potential, as well as the action potential duration (1). The TREK subfamily includes TREK-1, TREK-2 and TRAAK. TREK-1 is predominantly expressed in the central and peripheral nervous system, with a particularly strong expression during early development TREK-1 is activated by membrane stretch and cell swelling (2). In the inside-out patch configuration, negative pressure is significantly more effective than positive pressure, suggesting that a specific membrane deformation (convex curving) preferentially opens TREK-1 (2). Mechanical force is transmitted directly to the channel via the lipid bilayer. Intracellular acidosis strongly sensitizes TREK-1 to membrane stretch, leading to channel opening at atmospheric pressure (3). TREK-1 is reversibly opened by polyunsaturated fatty acids (PUFA), including arachidonic acid (AA) (2). Activation of TREK-1 by AA in the excised patch configuration indicates that the effect is direct by interacting either with the channel protein or by partitioning into the lipid bilayer. Anionic amphipaths, including AA, insert in the outer leaflet of the bilayer and cause a convex curving of the membrane that opens TREK-1. On the contrary, the cationic amphipaths, including chlorpromazine (CPZ) and the local anesthetic tetracaine, insert in the negatively charged inner leaflet and reverse TREK-1 activation (2). Lysophospholipids (LP) including lysophosphatidylcholine (LPC), open TREK-1. The conic shape, rather than the charge of the molecule, is important for lysophospholipid activation. Other membrane phospholipids including PIP2, are also potent openers of TREK-1 (4). The recent invalidation of TREK-1 in a mouse model demonstrates that it is important for neuroprotection against epilepsy and ischemia. Futhermore, TREK-1 -/- mice are also more resistant to volatile general anesthetics, indicating a role for TREK-1 in the mechanism of general anesthesia (5). Mutagenesis studies have determined that the cytosolic carboxy terminal domain of TREK-1 plays a key role in TREK-1 gating by both physical and chemical stimuli (2,3). Protonation of a key residue in this region, E306, leads to channel activation (3). Interaction of the carboxy terminal domain of TREK-1 with phospholipids in the inner leaflet of the lipid bilayer is enhanced by protonation of E306 and sensitizes TREK-1 to membrane stretch (3, 4). Conversely, down-modulation of TREK-1 is achieved by receptor- coupled protein kinase A (PKA) phosphorylation of residue S333 (2). In conclusion, the TREK and TRAAK channels are polymodal K channels that integrate multiple physical and chemical stimuli. Cellular lipids are key regulators of these channels that may play an important functional role in neuroprotection.