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.
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India.
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Harinath
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Sikdar
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