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Protein Crystallography under Xenon and Nitrous Oxide Pressure: Comparison with In Vivo Pharmacology Studies and Implications for the Mechanism of Inhaled Anesthetic Action

Nathalie Colloc'h ^*, Jana Sopkova-de Oliveira Santos , Pascal Retailleau , Denis Vivarès , Françoise Bonneté , Béatrice Langlois d'Estainto ^¶, Bernard Gallois ^¶, Alain Brisson ^¶, Jean-Jacques Risso ^||, Marc Lemaire ^**, Thierry Prangé  and Jacques H. Abraini ^* 

^* Centre CYCERON, UMR 6185, Université de Caen – CNRS, 14074 Caen cedex, France; Université de Caen, UPRES-EA 2126 (CERMN)- UFR Sciences Pharmaceutiques, 14000 Caen, France; Institut de Chimie des Substances Naturelles (CNRS), 91198 Gif-sur-Yvette Cedex, France; CRMCN-CNRS, Université de la Méditerranée, Marseille, France; ^¶ UMR-5471 Biophysique Structurale, Université Bordeaux 1, 33405 Talence, France; ^|| Institut de Médecine Navale du Service de Santé des Armées, HIA Ste-Anne, BP 610, 83800 Toulon Naval, France; ^** Air Liquide Research and Development, Claude-Delorme Research Centre, 78354, Jouy-en-Josas, France; LCRB, UMR CNRS 8015, Faculté de Pharmacie, 75270 Paris cedex 06, France; and NNOXe Pharmaceuticals Inc., Québec, QC G1W 4W5, Canada

Correspondence: Address reprint requests to Dr. Nathalie Colloc'h, Centre CYCERON, UMR 6185 Université de Caen-CNRS, Bd Becquerel, 14074 Caen cedex, France. Fax: 33-2-31-47-02-22; E-mail: colloch{at}cyceron.fr; or to Pr. Jacques H. Abraini; Fax: 33-2-31-47-01-02; E-mail: abraini{at}cyceron.fr.

In contrast with most inhalational anesthetics, the anesthetic gases xenon (Xe) and nitrous oxide (N₂O) 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 N₂O were determined. One N₂O molecule or one Xe atom binds to the same main site in both proteins. A second subsite is observed for N₂O in each case. The gas-binding sites are always hydrophobic flexible cavities buried within the monomer. Comparison of the effects of Xe and N₂O 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.

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