title: General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.
abstract: General anesthetics are widely used in clinical practice. On the molecular level, these compounds have been shown to modulate the activity of various neuronal ion channels. However, the functional relevance of identified sites in mediating essential components of the general anesthetic state, such as immobility and hypnosis, is still unknown. Using gene-targeting technology, we generated mice harboring a subtle point mutation (N265M) in the second transmembrane region of the beta3 subunit of the GABA(A) receptor. In these mice, the suppression of noxious-evoked movements in response to the intravenous anesthetics etomidate and propofol is completely abolished, while only slightly decreased with the volatile anesthetics enflurane and halothane. beta3(N265M) mice also display a profound reduction in the loss of righting reflex duration in response to intravenous but not volatile anesthetics. In addition, electrophysiological recordings revealed that anesthetic agents were significantly less effective in enhancing GABA(A) receptor-mediated currents, and in decreasing spontaneous action potential firing in cortical brain slices derived from mutant mice. Taken together, our results demonstrate that a single molecular target, and indeed a specific residue (N265) located within the GABA(A) receptor beta3 subunit, is a major determinant of behavioral responses evoked by the intravenous anesthetics etomidate and propofol, whereas volatile anesthetics appear to act via a broader spectrum of molecular targets.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zürich, CH-8057 Zürich, Switzerland.
authors.forename: Rachel
authors.initials: R
authors.lastname: Jurd
authors.forename: Margarete
authors.initials: M
authors.lastname: Arras
authors.forename: Sachar
authors.initials: S
authors.lastname: Lambert
authors.forename: Berthold
authors.initials: B
authors.lastname: Drexler
authors.forename: Roberta
authors.initials: R
authors.lastname: Siegwart
authors.forename: Florence
authors.initials: F
authors.lastname: Crestani
authors.forename: Michael
authors.initials: M
authors.lastname: Zaugg
authors.forename: Kaspar E
authors.initials: KE
authors.lastname: Vogt
authors.forename: Birgit
authors.initials: B
authors.lastname: Ledermann
authors.forename: Bernd
authors.initials: B
authors.lastname: Antkowiak
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
mesh_terms: D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004737:Enflurane / Q000494:pharmacology; D005045:Etomidate / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D017354:Point Mutation; D015742:Propofol / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*
chemical_list: D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D021122:Protein Subunits; D011963:Receptors, GABA-A; D004737:Enflurane; D006221:Halothane; D015742:Propofol; D005045:Etomidate