Multiple modalities converge on a common gate to control K2P channel function

Members of the K 2P potassium channel family regulate neuronal excitability and are implicated in pain, anaesthetic responses, thermosensation, neuroprotection, and mood. Unlike other potassium channels, K 2P s are gated by remarkably diverse stimuli that include chemical, thermal, and mechanical modalities. It has remained unclear whether the various gating inputs act through separate or common channel elements. Here, we show that protons, heat, and pressure affect activity of the prototypical, polymodal K 2P , K 2P 2.1 ( KCNK2 /TREK‐1), at a common molecular gate that comprises elements of the pore‐forming segments and the N‐terminal end of the M4 transmembrane segment. We further demonstrate that the M4 gating element is conserved among K 2P s and is employed regardless of whether the gating stimuli are inhibitory or activating. Our results define a unique gating mechanism shared by K 2P family members and suggest that their diverse sensory properties are achieved by coupling different molecular sensors to a conserved core gating apparatus. K 2P potassium channels play important roles in the regulation of neuronal excitability. K 2P channels are gated chemical, thermal, and mechanical stimuli, and the present study identifies and characterizes a common molecular gate that responds to all different stimuli, both activating and inhibitory ones.