Transmembrane Helix Straightening and Buckling Underlies Activation of Mechanosensitive and Thermosensitive K-2P Channels

Mechanical and thermal activation of ion channels is central to touch,
thermosensation, and pain. The TRAAK/TREK K-2P 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 K(2P)4.1 (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 K-2P modulation,
indicate a means for how the K-2P C-terminal cytoplasmic domain affects
the C-type gate which lies similar to 40 angstrom away, and suggest how
lipids and bilayer inner leaflet deformations may gate the channel.