Potent activation of the human tandem pore domain K channel TRESK with clinical concentrations of volatile anesthetics.
The tandem pore domain K channel family mediates background K currents present in excitable cells. Currents passed by certain members of the family are enhanced by volatile anesthetics, thus suggesting a novel mechanism of anesthesia. The newest member of the family, termed TRESK (TWIK [tandem pore domain weak inward rectifying channel]-related spinal cord K channel), has not been studied for anesthetic sensitivity. We isolated the coding sequence for TRESK from human spinal cord RNA and functionally expressed it in Xenopus oocytes and transfected COS-7 cells. With both whole-cell voltage-clamp and patch-clamp recording, TRESK currents increased up to three-fold by clinical concentrations of isoflurane, halothane, sevoflurane, and desflurane. Nonanesthetics (nonimmobilizers) had no effect on TRESK. Various IV anesthetics, including etomidate, thiopental, and propofol, have a minimal effect on TRESK currents. Amide and ester local anesthetics inhibit TRESK in a concentration-dependent manner but at concentrations generally larger than those that inhibit other tandem pore domain K channels. We also determined that TRESK is found not only in spinal cord, but also in human brain RNA. These results identify TRESK as a target of volatile anesthetics and suggest a role for this background K channel in mediating the effects of inhaled anesthetics in the central nervous system.
Liu
Canhui
C
Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California.
Au
John D
JD
Zou
Hilary Liao
HL
Cotten
Joseph F
JF
Yost
C Spencer
CS
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009841:Oligonucleotides / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists* / Q000235:genetics; D024683:Potassium Channels, Tandem Pore Domain / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000378:metabolism; D014982:Xenopus laevis
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D000779:Anesthetics, Local; C476574:KCNK18 protein, human; C410295:KCNK5 protein, human; D009841:Oligonucleotides; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D018075:RNA, Complementary; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases