Motoneuronal TASK channels contribute to immobilizing effects of inhalational general anesthetics.
General anesthetics cause sedation, hypnosis, and immobilization via CNS mechanisms that remain incompletely understood; contributions of particular anesthetic targets in specific neural pathways remain largely unexplored. Among potential molecular targets for mediating anesthetic actions, members of the TASK subgroup [TASK-1 (K2P3.1) and TASK-3 (K2P9.1)] of background K(+) channels are appealing candidates since they are expressed in CNS sites relevant to anesthetic actions and activated by clinically relevant concentrations of inhaled anesthetics. Here, we used global and conditional TASK channel single and double subunit knock-out mice to demonstrate definitively that TASK channels account for motoneuronal, anesthetic-activated K(+) currents and to test their contributions to sedative, hypnotic, and immobilizing anesthetic actions. In motoneurons from all knock-out mice lines, TASK-like currents were reduced and cells were less sensitive to hyperpolarizing effects of halothane and isoflurane. In an immobilization assay, higher concentrations of both halothane and isoflurane were required to render TASK knock-out animals unresponsive to a tail pinch; in assays of sedation (loss of movement) and hypnosis (loss-of-righting reflex), TASK knock-out mice showed a modest decrease in sensitivity, and only for halothane. In conditional knock-out mice, with TASK channel deletion restricted to cholinergic neurons, immobilizing actions of the inhaled anesthetics and sedative effects of halothane were reduced to the same extent as in global knock-out lines. These data indicate that TASK channels in cholinergic neurons are molecular substrates for select actions of inhaled anesthetics; for immobilization, which is spinally mediated, these data implicate motoneurons as the likely neuronal substrates.
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908-0735, USA.
Roman M
RM
Lazarenko
Sarah C
SC
Willcox
Shaofang
S
Shu
Allison P
AP
Berg
Vesna
V
Jevtovic-Todorovic
Edmund M
EM
Talley
Xiangdong
X
Chen
Douglas A
DA
Bayliss
D000704:Analysis of Variance; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D001933:Brain Stem / Q000166:cytology; D002461:Cell Line, Transformed; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D017353:Gene Deletion; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046353:Immobility Response, Tonic / Q000187:drug effects*; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D024683:Potassium Channels, Tandem Pore Domain / Q000172:deficiency / Q000378:metabolism*
D018685:Anesthetics, Inhalation; C498739:Kcnk5 protein, mouse; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D007530:Isoflurane; D002795:Choline O-Acetyltransferase; D006221:Halothane