Two-Pore Domain Potassium Channels as Drug Targets: Anesthesia and Beyond

Abstract

Two-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 8, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

K 2P channel C-type gating involves asymmetric selectivity filter order-disorder transitions

“…Such asymmetric changes could contribute to the bimodal distribution of closed state dwell times reported for K 2P 2.1-(TREK-1) (47) and the closely-related K 2P 10.1 (TREK-2) (48). Further, as K 2P heterodimer formation yields channels having two unique SF1-M2 and SF2-M4 loops, this structural diversification together with the two nonmutually exclusive inactivation modes likely provides a mechanism for the emergence of heterodimer properties that differ from either homodimer parent (49)(50)(51)(52)(53)(54)(55)(56). The structural rearrangements in the pore and surrounding regions, loss of S1 and S2 ions, and the demonstration that destabilization of the SF2-M4 loop structure compromises ion selectivity are reminiscent of studies of the nonselective bacterial channel NaK, which has only the S3 and S4 sites and can be converted into a potassium-selective channel by forming the S1 and S2 ion binding sites (27).…”

Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092

“…Lamotrigine and the novel compound CEN-092, on the other hand, are less effective inhibitors of all three channels tested, but CEN-092 is significantly more effective at inhibiting TRESK than TREK channels. Given the paucity of selective antagonists of K2P channels [ 4 ], this study helps clarify the action of sipatrigine and lamotrigine on TREK and TRESK channels and, through, the comparative selectivity for the novel blocking agent CEN-092 for TRESK over TREK channels provides the potential for the development of more selective blocking agents in the future.…”

“…The TWIK-related potassium channels (TREK-1 and TREK-2) and TWIK-related spinal cord potassium channel (TRESK) belong to the two-pore domain (K2P) family of ion channels, whose main functional role is to regulate cellular excitability [ 1 ]. TREK-1 and TREK-2 are highly expressed in small nociceptor dorsal root ganglion (DRG) and have been shown to play an active role in neuroprotection, schizophrenia, depression, and pain, whilst TRESK, with similar high expression in sensory neurons, has a role in nociception and migraine [ [1] , [2] , [3] , [4] ]. Compounds which alter the activity of these channels are therefore predicted to have therapeutic potential in treating CNS disorders.…”

“…Compounds which alter the activity of these channels are therefore predicted to have therapeutic potential in treating CNS disorders. Indeed, TREK-1 and TREK-2, channel activity has been shown to be regulated by antidepressants, antipsychotics, mood stabilizers, anaesthetics and neuroprotective agents [ [4] , [5] , [6] , [7] , [8] , [9] ]. TRESK channels have been shown to be regulated by volatile anaesthetics [ 10 ], anti-depressant and anti-convulsant agents [ 11 ] and antihistamines [ 12 ].…”

Clinical Importance of the Human Umbilical Artery Potassium Channels

“…Indeed, there are relatively few selective antagonists for the TREK channels. Some examples of blockers include chlorpromazine, sipatrigine, fluoxetine, and norfluoxetine [ 209 ]. However, there is currently a highly specific and fast-acting inhibitor on TREK-1 channels, spadin.…”