Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Abstract

Recent evidence points to a pivotal contribution of a variety of different potassium channels, including two-pore domain potassium (K2P) channels, in chronic pain processing. Expression of several different K2P channel subunits has been detected in nociceptive dorsal root ganglion neurons and trigeminal ganglion neurons, in particular, TREK1, TREK2, TRESK, TRAAK, TASK3 and TWIK1 channels. Of these, the strongest body of evidence from functional studies highlights the importance of TREK1, TRESK and, recently, TREK2 channels. For example, TREK1 knockout mice are more sensitive than wild-type mice to a number of painful stimuli but less sensitive to morphine-induced analgesia. TRESK knockdown mice show behavioural evidence of increased pain and increased sensitivity to painful pressure. Importantly, familial migraine with aura is associated with a dominant-negative mutation in human TRESK channels. Thus, the functional up-regulation of K2P channel activity may be a useful strategy in the development of new therapies for the treatment of pain. Whilst there are few currently available compounds that selectively and directly enhance the activity of TRESK and TREK2 channels, recent advances have been made in terms of identifying compounds that activate TREK1 channels and in understanding how they might act on the channel. Large-scale bio-informatic approaches and the further development of databases of putative ligands, channel structures and putative ligand binding sites on these structures may form the basis for future experimental strategies to detect novel molecules acting to enhance K2P channel activity that would be useful in the treatment of pain.

Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel

“…They are widely expressed in both the central and peripheral nervous system and, in addition to their mechanosensitivity, are regulated by a wide range of other biological, chemical, and physical stimuli including pH, temperature, lipids, and anesthetics. Such “polymodal” regulation allows these channels to integrate many different signaling pathways to control membrane excitability including several nociceptive pathways (Mathie and Veale, 2015, Pereira et al., 2014). Crystal structures have now been determined for all three of these mechanosensitive K2P channels as well as for the non-mechanosensitive channel, TWIK-1 (Brohawn et al., 2012, Dong et al., 2015, Miller and Long, 2012).…”

Expression and localisation of two-pore domain (K2P) background leak potassium ion channels in the mouse retina

“…36). K2P channels have been assigned prominent roles in many physiological systems, including cardiovascular3738, pain3940, respiration41, hearing4243, taste44, anaesthesia224546 and sleep474849. K2P channels have also been implicated in a number of pathological conditions, including autoimmune and degenerative diseases50, tumourgenesis5152, mental retardation (Barel-Birk-syndrome)53, migraine54, ischemia465556, epilepsy46 and depression465758.…”

Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx

“…3,4,7,8 Indeed, molecules that activate TREK-2 channels have been found to reduce pain. 8 For example, aristolochic acid from plant extracts is a traditional medicine for treating pain and activates TREK-2.…”