Protein crystallography under xenon and nitrous oxide pressure: Comparison with in vivo pharmacology studies and implications for the mechanism of inhaled anesthetic action

¹ CNRS UMR 6185, Centre Cyceron
² UPRES-EA 2126, CERMN
³ Institut de Chimie des Substances Naturelles, CNRS
⁴ Institut de Médecine Navale du Service de Santé des Armées
⁵ Air Liquide Research and Development
⁶ LCRB, UMR CNRS 8015

^* To whom correspondence should be addressed. E-mail: colloch{at}cyceron.fr.

Submitted on July 21, 2006
Revised on August 18, 2006
Accepted on 6 September 2006

	Abstract

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 possesses 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 gas 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, while additional alterations of ion-channel membrane receptor functions are required for deeper effects that progress to "surgical" anesthesia.

Key Words: X-ray crystallography, anesthesia mechanism, annexin V, hydrophobic cavity, inhaled anesthesic, urate oxidase

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