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

Abstract

TREK‐1 (KCNK2 or K2P2.1) is a mechanosensitive K2P 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 carboxy‐terminal 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‐, pHi‐ and voltage‐dependent gating.