title: Impact of Hyperpolarization-activated, Cyclic Nucleotide-gated Cation Channel Type 2 for the Xenon-mediated Anesthetic Effect: Evidence from In Vitro and In Vivo Experiments.
abstract: BACKGROUND
  The thalamus is thought to be crucially involved in the anesthetic state. Here, we investigated the effect of the inhaled anesthetic xenon on stimulus-evoked thalamocortical network activity and on excitability of thalamocortical neurons. Because hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are key regulators of neuronal excitability in the thalamus, the effect of xenon on HCN channels was examined.
  
  
  METHODS
  The effects of xenon on thalamocortical network activity were investigated in acutely prepared brain slices from adult wild-type and HCN2 knockout mice by means of voltage-sensitive dye imaging. The influence of xenon on single-cell excitability in brain slices was investigated using the whole-cell patch-clamp technique. Effects of xenon on HCN channels were verified in human embryonic kidney cells expressing HCN2 channels.
  
  
  RESULTS
  Xenon concentration-dependently diminished thalamocortical signal propagation. In neurons, xenon reduced HCN channel-mediated Ih current amplitude by 33.4 ± 12.2% (at -133 mV; n = 7; P = 0.041) and caused a left-shift in the voltage of half-maximum activation (V1/2) from -98.8 ± 1.6 to -108.0 ± 4.2 mV (n = 8; P = 0.035). Similar effects were seen in human embryonic kidney cells. The impairment of HCN channel function was negligible when intracellular cyclic adenosine monophosphate level was increased. Using HCN2 mice, we could demonstrate that xenon did neither attenuate in vitro thalamocortical signal propagation nor did it show sedating effects in vivo.
  
  
  CONCLUSIONS
  Here, we clearly showed that xenon impairs HCN2 channel function, and this impairment is dependent on intracellular cyclic adenosine monophosphate levels. We provide evidence that this effect reduces thalamocortical signal propagation and probably contributes to the hypnotic properties of xenon.
authors.affiliation: From the Department of Anesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (C.M., S.K., M. Buerge, M.K., T.E., C.K., E.K., R.H., G.R.); Department Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Munich, Germany (M. Biel, V.H.); and Department of Anesthesiology, Weill Cornell Medical College, New York, New York (S.-W.Y., P.A.G.).
authors.forename: Corinna
authors.initials: C
authors.lastname: Mattusch
authors.forename: Stephan
authors.initials: S
authors.lastname: Kratzer
authors.forename: Martina
authors.initials: M
authors.lastname: Buerge
authors.forename: Matthias
authors.initials: M
authors.lastname: Kreuzer
authors.forename: Tatiana
authors.initials: T
authors.lastname: Engel
authors.forename: Claudia
authors.initials: C
authors.lastname: Kopp
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.forename: Verena
authors.initials: V
authors.lastname: Hammelmann
authors.forename: Shui-Wang
authors.initials: SW
authors.lastname: Ying
authors.forename: Peter A
authors.initials: PA
authors.lastname: Goldstein
authors.forename: Eberhard
authors.initials: E
authors.lastname: Kochs
authors.forename: Rainer
authors.initials: R
authors.lastname: Haseneder
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rammes
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000187:drug effects* / Q000235:genetics; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics; D013788:Thalamus / Q000166:cytology / Q000187:drug effects; D014978:Xenon / Q000494:pharmacology*
chemical_list: D018685:Anesthetics, Inhalation; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D014978:Xenon; D000242:Cyclic AMP