title: An allosteric coagonist model for propofol effects on α1β2γ2L γ-aminobutyric acid type A receptors.
abstract: BACKGROUND
  Propofol produces its major actions via γ-aminobutyric acid type A (GABA(A)) receptors. At low concentrations, propofol enhances agonist-stimulated GABA(A) receptor activity, and high propofol concentrations directly activate receptors. Etomidate produces similar effects, and there is convincing evidence that a single class of etomidate sites mediate both agonist modulation and direct GABA(A) receptor activation. It is unknown if the propofol binding site(s) on GABA(A) receptors that modulate agonist-induced activity also mediate direct activation.
  
  
  METHODS
  GABA(A) α1β2γ2L receptors were heterologously expressed in Xenopus oocytes and activity was quantified using voltage clamp electrophysiology. We tested whether propofol and etomidate display the same linkage between agonist modulation and direct activation of GABA(A) receptors by identifying equiefficacious drug solutions for direct activation. We then determined whether these drug solutions produce equal modulation of GABA-induced receptor activity. We also measured propofol-dependent direct activation and modulation of low GABA responses. Allosteric coagonist models similar to that established for etomidate, but with variable numbers of propofol sites, were fitted to combined data.
  
  
  RESULTS
  Solutions of 19 μM propofol and 10 μM etomidate were found to equally activate GABA(A) receptors. These two drug solutions also produced indistinguishable modulation of GABA-induced receptor activity. Combined electrophysiological data behaved in a manner consistent with allosteric coagonist models with more than one propofol site. The best fit was observed when the model assumed three equivalent propofol sites.
  
  
  CONCLUSIONS
  Our results support the hypothesis that propofol, like etomidate, acts at GABA(A) receptor sites mediating both GABA modulation and direct activation.
authors: Department of Anesthesia and Intensive Care, University Hospital Giessen-Marburg, Marburg, Germany.
authors: Dirk
authors: D
authors: Ruesch
authors: Elena
authors: E
authors: Neumann
authors: Hinnerk
authors: H
authors: Wulf
authors: Stuart A
authors: SA
authors: Forman
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002417:Cattle; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000494:pharmacology; D005260:Female; D018755:GABA Agonists; D006801:Humans; D015233:Models, Statistical; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010957:Plasmids / Q000235:genetics; D015742:Propofol / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018686:Anesthetics, Intravenous; D018755:GABA Agonists; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D004247:DNA; D015742:Propofol; D005045:Etomidate