Az orvos-, egészségtudományi- és gyógyszerészképzés tudományos műhelyeinek fejlesztése(EFOP-3.6.3-VEKOP-16-2017-00009)
Támogató: EFOP-VEKOP
Szakterületek:
Általános orvostudomány
Orvos- és egészségtudomány
Cloxyquin has been reported as a specific activator of TRESK (K2P18.1, TWIK-related
spinal cord K+ channel) background potassium channel. In this study, we have synthetized
chemically modified analogues of cloxyquin and tested their effects on TRESK and other
K2P channels. The currents of murine K2P channels, expressed heterologously in Xenopus
oocytes, were measured by two-electrode voltage clamp, whereas the native background
K+ conductance of mouse dorsal root ganglion (DRG) neurons was examined by the whole-cell
patch clamp method. Some of the analogues retained the activator character of the
parent compound, but more interestingly, other derivatives inhibited mouse TRESK current.
The inhibitor analogues (A2764 and A2793) exerted state-dependent effect. The degree
of inhibition by 100 µM A2764 (77.8±1.5%, n=6) was larger in the activated state of
TRESK (i.e. after calcineurin-dependent stimulation) than in the resting state of
the channel (42.8±4.3% inhibition, n=7). The selectivity of the inhibitor compounds
was tested on several K2P channels. A2793 inhibited TASK-1 (100 µM, 53.4±6%, n=5),
while A2764 was more selective for TRESK, it only moderately influenced TREK-1 and
TALK-1. The effect of A2764 was also examined on the background K+ currents of DRG
neurons. A subpopulation of DRG neurons, prepared from wild-type animals, expressed
background K+ currents sensitive to A2764, while the inhibitor did not affect the
currents in the DRG neurons of TRESK-deficient mice. Accordingly, A2764 may prove
to be useful for the identification of TRESK current in native cells, and for the
investigation of the role of the channel in nociception and migraine.
