Abstract

Polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channels of the TREK subfamily generate ‘leak’ currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. In contrast to other potassium channels, K2P channels use a selectivity filter ‘C-type’ gate as the principal gating site. K2P channels stuffer from a poor pharmacological profiles that has limited mechanistic and biological studies. We recently discovered a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges. Structural studies of K2P2 .1 (TREK-1) alone and with two selective activators unmask a cryptic binding pocket unlike other ion channel small-molecule binding sites. Our work defines a druggable K2P site that stabilizes the C-type gate ‘leak mode’ and provides direct evidence for K2P selectivity filter gating. Our studies define a new means for ion channel control and offer a new direction for developing a chemical biology for K2P channels.