Protein crystallography under xenon and nitrous oxide pressure: comparison with in vivo pharmacology studies and implications for the mechanism of inhaled anesthetic action.
In contrast with most inhalational anesthetics, the anesthetic gases xenon (Xe) and nitrous oxide (N(2)O) act by blocking the N-methyl-d-aspartate (NMDA) receptor. Using x-ray crystallography, we examined the binding characteristics of these two gases on two soluble proteins as structural models: urate oxidase, which is a prototype of a variety of intracellular globular proteins, and annexin V, which has structural and functional characteristics that allow it to be considered as a prototype for the NMDA receptor. The structure of these proteins complexed with Xe and N(2)O were determined. One N(2)O molecule or one Xe atom binds to the same main site in both proteins. A second subsite is observed for N(2)O in each case. The gas-binding sites are always hydrophobic flexible cavities buried within the monomer. Comparison of the effects of Xe and N(2)O on urate oxidase and annexin V reveals an interesting relationship with the in vivo pharmacological effects of these gases, the ratio of the gas-binding sites' volume expansion and the ratio of the narcotic potency being similar. Given these data, we propose that alterations of cytosolic globular protein functions by general anesthetics would be responsible for the early stages of anesthesia such as amnesia and hypnosis and that additional alterations of ion-channel membrane receptor functions are required for deeper effects that progress to "surgical" anesthesia.
Colloc'h
Nathalie
N
Centre CYCERON, UMR 6185, Université de Caen--CNRS, 14074 Caen cedex, France.
Sopkova-de Oliveira Santos
Jana
J
Retailleau
Pascal
P
Vivarès
Denis
D
Bonneté
Françoise
F
Langlois d'Estainto
Béatrice
B
Gallois
Bernard
B
Brisson
Alain
A
Risso
Jean-Jacques
JJ
Lemaire
Marc
M
Prangé
Thierry
T
Abraini
Jacques H
JH
D000777:Anesthetics / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000737:chemistry / Q000494:pharmacology*; D017304:Annexin A5 / Q000737:chemistry; D001231:Aspergillus flavus / Q000201:enzymology; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000295:instrumentation* / Q000379:methods*; D003600:Cytosol / Q000378:metabolism; D009609:Nitrous Oxide / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D011487:Protein Conformation; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry*; D014503:Urate Oxidase / Q000737:chemistry; D014978:Xenon / Q000737:chemistry*
D000777:Anesthetics; D018685:Anesthetics, Inhalation; D017304:Annexin A5; D016194:Receptors, N-Methyl-D-Aspartate; D014978:Xenon; D014503:Urate Oxidase; D009609:Nitrous Oxide; D010100:Oxygen