title: Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology.
abstract: BACKGROUND
  Inhibition of N-methyl-D-aspartate (NMDA) receptors by anesthetic gases and vapors may play an important role in anesthesia and neuroprotection. However, the site of action of these agents on the NMDA receptor is unknown. The authors show that xenon and isoflurane compete for the binding of the coagonist glycine on the NMDA receptor NR1 subunit.
  
  
  METHODS
  Using a novel application of grand canonical Monte Carlo simulations, the authors predict the binding site of xenon on NMDA receptors. They test this prediction using electrophysiology on recombinant NMDA receptors.
  
  
  RESULTS
  The authors' modeling predicts that xenon binds at the glycine site of the NMDA receptor. The authors show that inhibition of NMDA receptors by xenon and isoflurane increases as glycine concentration is decreased, consistent with the prediction of competitive inhibition at the glycine site. Lineweaver-Burk analysis shows that isoflurane inhibition seems purely competitive with glycine, but for xenon, there is an additional component of noncompetitive inhibition. The loss of inhibitory effect of xenon and isoflurane in mutant NR1(F639A)/NR2A receptors is explained by increased glycine affinity of the mutant receptors, and inhibition is restored at low glycine concentrations.
  
  
  CONCLUSIONS
  Xenon and isoflurane inhibit NMDA receptors by binding at the same site as the coagonist glycine. This finding may have important implications for general anesthesia and neuroprotection. Neuroprotectants that act at the glycine site of the NMDA receptor antagonists are well tolerated in patients, being devoid of psychotomimetic side effects, and the mechanism of inhibition may play a role in their clinical profile.
authors: Blackett Laboratory, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom. r.dickinson@imperial.ac.uk
authors: Robert
authors: R
authors: Dickinson
authors: Brian K
authors: BK
authors: Peterson
authors: Paul
authors: P
authors: Banks
authors: Constantinos
authors: C
authors: Simillis
authors: Juan Carlos Sacristan
authors: JC
authors: Martin
authors: Carlos A
authors: CA
authors: Valenzuela
authors: Mervyn
authors: M
authors: Maze
authors: Nicholas P
authors: NP
authors: Franks
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D018929:Cell Culture Techniques; D004594:Electrophysiology; D005998:Glycine / Q000187:drug effects*; D007530:Isoflurane / Q000494:pharmacology*; D008958:Models, Molecular; D009010:Monte Carlo Method; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000187:drug effects*; D014978:Xenon / Q000494:pharmacology*
chemical_list: D018685:Anesthetics, Inhalation; D016194:Receptors, N-Methyl-D-Aspartate; D014978:Xenon; D007530:Isoflurane; D005998:Glycine