Transmembrane Helix Straightening and Buckling Underlies Activation of Mechanosensitive and Thermosensitive K2P Channels

Mechanical and thermal activation of ion channels is central to touch, thermosensation, and pain. The TRAAK/TREK K2P potassium channel subfamily produces background currents that alter neuronal excitability in response to pressure, temperature, signaling lipids, and anesthetics. How such diverse stimuli control channel function is unclear. Here we report structures of K2P4.1 (TRAAK) bearing C-type gate-activating mutations that reveal a tilting and straightening of the M4 inner transmembrane helix and a buckling of the M2 transmembrane helix. These conformational changes move M4 in a direction opposite to that in classical potassium channel activation mechanisms and open a passage lateral to the pore that faces the lipid bilayer inner leaflet. Together, our findings uncover a unique aspect of K2P modulation, indicate a means for how the K2P C-terminal cytoplasmic domain affects the C-type gate which lies ∼40Å away, and suggest how lipids and bilayer inner leaflet deformations may gate the channel. •K2P4.1 (TRAAK) activation involves M2 and M4 helix movement•M4 helix movements are opposite to classic channel-gating mechanisms•M4 movement is concomitant with a buckling of M2 at a conserved GXG sequence•Quaternary changes open a lateral opening to inner bilayer leaflet Understanding how physical forces such as temperature and pressure gate ion channels remains unclear. Lolicato et al. describe structures of activated mutants of K2P4.1 (TRAAK), a mechanosensitive K2P potassium channel, that uncover conformational changes central to K2P channel gating.