Lysophospholipids open the two-pore domain mechano-gated K+ channels TREK-1 and TRAAK

The two-pore (2P) domain K+ channels TREK-I and TRAAK are opened by membran e stretch as well as arachidonic acid (AA) (Patel, A. J., Honore, E., Maing ret, F., Lesage, F., Fink, M., Duprat, F., and Lazdunski, M. (1998) EMBO J. 17, 4283-4290; Maingret, F., Patel, A. J., Lesage, F., Lazdunski, M., and Honore, E. (1999) J. Biol. Chem 274, 26691-26696; Maingret, F., Fosset, M., Lesage, F., Lazdunski, M., and Honore, E. (1999) J. Biol. Chem. 274, 1381- 1387. me demonstrate that lysophospholipids (LPs) and platelet-activating f actor also produce large specific and reversible activations of TREK-I and TRAAK. LPs activation is a function of the size of the polar head and lengt h of the acyl chain but is independent of the charge of the molecule. Bath application of lysophosphatidylcholine (LPC) immediately opens TREK-1 and T RAAK in the cell-attached patch configuration. In excised patches, LPC acti vation is lost, whereas AA still produces maximal opening. The carboxyl-ter minal region of TREK-I, but not the amino terminus and the extracellular lo op M1P1, is critically required for LPC activation. LPC activation is indir ect and may possibly involve a cytosolic factor, whereas AA directly intera cts with either the channel proteins or the bilayer and mimics stretch. Ope ning of TREK-1 and TRAAK by fatty acids and LPs may be an important switch in the regulation of synaptic function and may also play a protective role during ischemia and inflammation.