Protons, Heat, and Mechanical Force Act Through a Common Gate to Control K 2P Channel Function

Abstract

Members of the K2P potassium channel family are key regulators of cell excitability and are implicated in pain, anesthetic responses, thermosensation, neuroprotection, and mood. Unlike other potassium channel families, K2P channels 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 the activity of the prototypical, polymodal K2P channel, K2P2.1 (KCNK2/TREK-1), at a common molecular gate that comprises extracellular elements of the pore-forming segments and part of the putative fourth transmembrane helix, M4, that is proximal to the extracellular end. We further demonstrate that the functional importance of the M4 gating element is conserved across the K2P family, regardless of whether the gating stimuli are inhibitory or activating. Taken together, our results highlight a unique gating mechanism shared by K2P channels and suggest that the diverse sensory properties of K2P channels are achieved by coupling different molecular sensors to a conserved core gating apparatus comprising the selectivity filter and M4.