Fig. 1. The K_2P channel family. (a) Dendrogram of K_2P channels with their physiological or pharmacological key modulators. TWIK: Tandem of P-domains in a weak inward rectifying K⁺ channel, TREK: TWIK-related K⁺ channel, TRAAK: TWIK-related arachidonic acid activated K⁺ channel, TASK: TWIK-related acid-sensitive K⁺ channel, TALK: TWIK-related alkaline activated K⁺ channel, THIK: TWIK-related halothane inhibited K⁺ channel, TRESK: TWIK-related spinal cord K⁺ channel. (b) Membrane topology of K_2P channels depicting transmembrane domains in blue, the pore helices in red and the extracellular 'cap' structure in purple. (c) Illustration of the crystal structure of the K_2P channel TWIK-1 (PDB ID: 3UKM). Transmembrane domains are illustrated in blue, the pore helices in red and the extracellular 'cap' structure in purple. (d) Illustration of the conserved scheme of drug binding sites in voltage gated ion channels. The typical binding sites of classical pore blockers are indicated with purple stars. CC: central cavity; SF: selectivity filter (e) Chemical formula of quaternary ammonium compounds, which are classical pore blockers with different alkyl side chain lengths.