1.A.1.9.1
TREK-1 (KCNK2) K⁺ channel subunit (Regulated by group 1 metabotropic glutamate receptors and by diacylglycerols and phosphatidic acids) (Chemin et al., 2003). TREK-1, TREK-2 and TRAAK are all regulated by lysophosphatidic acid, converting these mechano-gated, pH voltage-sensitive channels into leak conductances (Chemin et al., 2005). The mammalian K2P2.1 potassium channel (TREK-1, KCNK2) is highly expressed in excitable tissues, where it plays a key role in the cellular mechanisms of neuroprotection, anaesthesia, pain perception and depression (Cohen et at., 2008). Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium (Thomas et al. 2008). The crystal structure of the human 2-pore domain K⁺ channel, K2P1 has been solved (Miller and Long, 2012). Multiple modalities converge on a common gate to control K2P channel function (Bagriantsev et al., 2011).  TREK-1 mediates fast and slow glutamate release in astrocytes upon GPCR activation (Woo et al. 2012). It is a mechanosensitive K⁺ channel, present in rat bladder myocytes, which is activated by swelling and arachidonic acid (Fukasaku et al. 2016). The M2-hinges of TREK-1 and TREK-2 channels control their macroscopic current, subcellular localization and gating (Zhuo et al. 2017). The human ortholog has acc # O95069 and has an additional N-terminal 15 aas. BL-1249, a compound from the fenamate class of nonsteroidal anti-inflammatory drugs, is known to activate K2P2.1(TREK-1), the founding member of the thermo- and mechanosensitive TREK subfamily (Pope et al. 2018). Spadin and arachidonic acid, are known to suppress and activate TREK-1 channels, respectively (Pappa et al. 2020). Membrane phospholipids control gating of the mechanosensitive potassium leak channel, TREK1 (Schmidpeter et al. 2023). A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals (Landra-Willm et al. 2023). TREK-1 is an anesthetic-sensitive K⁺ channel (Spencer et al. 2023).  Covalent chemogenetic K_2P channel activators have been developed (Deal et al. 2024).  K_2P potassium channels regulate excitability by affecting the cellular resting membrane potential in the brain, cardiovascular system, immune cells, and sensory organs. They are important in anesthesia, arrhythmia, pain, hypertension, sleep, and migraine headaches.  CATKLAMP (covalent activation of TREK family K⁺ channels to clamp membrane potential) leverages the discovery of a K_2P modulator pocket site that reacts with electrophile-bearing derivatives of a TREK subfamily small-molecule activator, ML335, to activate the channel irreversibly. Deal et al. 2024 showed that CATKLAMP can be used to probe fundamental aspects of K_2P function, as a switch to silence neuronal firing, and is applicable to all TREK subfamily members.  TWIK-related K+ (TREK-1) channels are involved in pain perception, and their pharmacological activation has potential for pain relief.  LPS2336, a TREK-1 channel activator which has potential for pain relief (Boyer et al. 2025).