Trichloroethanol enhances the activity of recombinant human TREK-1 and TRAAK channels.
Human TREK-1 and TRAAK (hTREK-1 and hTRAAK) are the recently cloned tandem pore-domain potassium channels that are highly expressed in the central nervous system (CNS). The roles of 2P domain K+ channels in general anesthesia and neuroprotection have been proposed recently. We have investigated the ability of 2,2,2-trichloroethanol (an active metabolite of the general anesthetic chloral hydrate (CH)) to modulate the activity of hTREK-1 and hTRAAK channels expressed heterologously in Chinese hamster ovary cells by using whole-cell patch-clamp recording. Trichloroethanol potentiated hTREK-1 and hTRAAK channel activity in a reversible, concentration-dependent manner. The parent compound CH also augmented the activity of both the channels reversibly. CH activation of hTREK-1 was transient followed by a rapid inhibition, whereas hTRAAK activation was not followed by inhibition. Deletions of the carboxy terminal domain (Delta89, Delta100 and Delta119) of hTREK-1 did not abolish sensitivity to TCE (20 mM) suggesting that C-terminal tail is not essential for the activation of hTREK-1 by TCE. The hTREK-1 currents consisted of an instantaneous and a time-dependent component. The time-dependent current was reduced by trichloroethanol (20 mM). Our findings identify TREK-1 and TRAAK channels as molecular targets for trichloroethanol and suggest that activation of these channels might contribute to the CNS depressant effects of CH.
Harinath
S
S
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India.
Sikdar
S K
SK
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
C503432:KCNK4 protein, human; C503434:Kcnk4 protein, rat; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D011994:Recombinant Proteins; C103742:potassium channel protein TREK-1; D005023:Ethylene Chlorohydrin; C005849:2,2,2-trichloroethanol