The Polysite Pharmacology of TREK K_2P Channels

K_2P (KCNK) potassium channels form "background" or "leak" currents that have critical roles in cell excitability control in the brain, cardiovascular system, and somatosensory neurons. Similar to many ion channel families, studies of K_2Ps have been limited by poor pharmacology. Of six K_2P subfamilies, the thermo- and mechanosensitive TREK subfamily comprising K_2P2.1 (TREK-1), K_2P4.1 (TRAAK), and K_2P10.1 (TREK-2) are the first to have structures determined for each subfamily member. These structural studies have revealed key architectural features that underlie K_2P function and have uncovered sites residing at every level of the channel structure with respect to the membrane where small molecules or lipids can control channel function. This polysite pharmacology within a relatively small (~70 kDa) ion channel comprises four structurally defined modulator binding sites that occur above (Keystone inhibitor site), at the level of (K_2P modulator pocket), and below (Fenestration and Modulatory lipid sites) the C-type selectivity filter gate that is at the heart of K_2P function. Uncovering this rich structural landscape provides the framework for understanding and developing subtype-selective modulators to probe K_2P function that may provide leads for drugs for anesthesia, pain, arrhythmia, ischemia, and migraine.