Selective and state‐dependent activation of TRESK (K_2P18.1) background potassium channel by cloxyquin

Abstract

Cloxyquin activates TRESK by a Ca /calcineurin-independent mechanism. The drug is specific for TRESK within the K channel family and useful for studying TRESK currents in native cells. The state-dependent pharmacological profile of this channel should be considered in the development of therapeutics for migraine and other nociceptive disorders.

Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K2P18.1) Background Potassium Channel

“…The A2797 compound activated mTRESK current about 4-fold at a 100 mM concentration. This degree of activation was similar to the previously reported effect of cloxyquin (Lengyel et al, 2017). However, as opposed to the relative selectivity of cloxyquin for TRESK in the K 2P family, A2797 also activated TREK-2, TASK-2, and TRAAK channels.…”

“…The stimulatory effect of cloxyquin was independent of the Ca 21 /calcineurin pathway, suggesting that cloxyquin is a direct activator of the channel. We have also shown that cloxyquin activates TRESK in isolated mouse DRG neurons (Lengyel et al, 2017). In the present study, we have produced 28 chemically modified analogs of cloxyquin and examined their effects on TRESK channels.…”

“…As another tool to achieve this goal, cloxyquin, an antiamoebic drug, was identified as a TRESK activator in a high-throughput screening (Wright et al, 2013). We have recently shown that cloxyquin is selective for TRESK in the K 2P family and can activate the background K 1 current in mouse DRG neurons (Lengyel et al, 2017). Nevertheless, a high concentration of cloxyquin (in the 50-100 mM range) was required for TRESK activation.…”

“…Modification of the hydroxyl sidechain in the chlorinated hydroxyquinoline parent molecule resulted in inhibitory derivatives. We have recently reported that cloxyquin showed state dependence in its effect; it was only able to activate TRESK in the resting state, but not when the channel was activated by the Ca 21 /calcineurin pathway (Lengyel et al, 2017). Intrigued by the possibility that our inhibitors also show statedependent effects, we determined the degree of inhibition by A2793 for both the resting mTRESK and the channels preactivated by application of the calcium ionophore ionomycin.…”

Insight into the Molecular Interaction of Cloxyquin (5-chloro-8-hydroxyquinoline) with Bovine Serum Albumin: Biophysical Analysis and Computational Simulation

“…Furthermore, cloxyquin-mediated potassium channel activation has been reported. It selectively targets TRESK (K 2P channel family) and substantially activates the background potassium current, suggested for further development to be a promising therapeutic ingredient for migraine and other types of nociceptive pain [7,8]. Recently, the neuroprotective effect of cloxyquin derivative (nitroxoline) has been reported in H 2 O 2 -induced human neuronal cells [9].…”