A phospholipid sensor controls mechanogating of the K+ channel TREK-1

TREK- 1 ( KCNK2 or K(2P)2.1) is a mechanosensitive K-2P channel that is opened by membrane stretch as well as cell swelling. Here, we demonstrate that membrane phospholipids, including PIP2, control channel gating and transform TREK- 1 into a leak K (+) conductance. A carboxyterminal positively charged cluster is the phospholipid-sensing domain that interacts with the plasma membrane. This region also encompasses the proton sensor E306 that is required for activation of TREK- 1 by cytosolic acidosis. Protonation of E306 drastically tightens channel - phospholipid interaction and leads to TREK- 1 opening at atmospheric pressure. The TREK- 1 - phospholipid interaction is critical for channel mechano-, pH(i)- and voltage- dependent gating.