title: Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane.
abstract: Nitrous oxide, xenon, and cyclopropane are anesthetic gases that have a distinct pharmacological profile. Whereas the molecular basis for their anesthetic actions remains unclear, they behave very differently to most other general anesthetics in that they have little or no effect on GABAA receptors, yet strongly inhibit the N-methyl-d-aspartate subtype of glutamate receptors. Here we show that certain members of the two-pore-domain K+ channel superfamily may represent an important new target for these gaseous anesthetics. TREK-1 is markedly activated by clinically relevant concentrations of nitrous oxide, xenon, and cyclopropane. In contrast, TASK-3, a member of this family that is very sensitive to volatile anesthetics, such as halothane, is insensitive to the anesthetic gases. We demonstrate that the C-terminal cytoplasmic domain is not an absolute requirement for the actions of the gases, although it clearly plays an important modulatory role. Finally, we show that Glu306, an amino acid that has previously been found to be important in the modulation of TREK-1 by arachidonic acid, membrane stretch and internal pH, is critical for the activating effects of the anesthetic gases.
authors.affiliation: Biophysics Section, Department of Biological Sciences, The Blackett Laboratory, Imperial College London, London, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Gruss
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Bushell
authors.forename: Damian P
authors.initials: DP
authors.lastname: Bright
authors.forename: William R
authors.initials: WR
authors.lastname: Lieb
authors.forename: Alistair
authors.initials: A
authors.lastname: Mathie
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Franks
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009609:Nitrous Oxide / Q000494:pharmacology*; D015221:Potassium Channels / Q000819:agonists / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain; D014978:Xenon / Q000494:pharmacology*
chemical_list: D018685:Anesthetics, Inhalation; D003521:Cyclopropanes; C498655:KCNK9 protein, human; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; D014978:Xenon; C030797:cyclopropane; D009609:Nitrous Oxide