Abstract
Xenon is frequently used as a general anesthetic in humans, but the mechanism remains an issue of debate. While for some membrane proteins, a direct interaction of xenon with the protein has been shown to be the inhibitory mechanism, other membrane protein functions could be affected by changes of membrane properties due to partitioning of the gas into the lipid bilayer. Here, the effect of xenon on a mechanosensitive ion channel and a copper ion-translocating ATPase was compared under different conditions. Xenon inhibited spontaneous gating of the Escherichia coli mechano-sensitive mutant channel MscL-G22E, as shown by patch-clamp recording techniques. Under high hydrostatic pressure, MscL-inhibition was reversed. Similarly, the activity of the Enterococcus hirae CopB copper ATPase, reconstituted into proteoliposomes, was inhibited by xenon. However, the CopB ATPase activity was also inhibited by xenon when CopB was in a solubilized state. These findings suggest that xenon acts by directly interacting with these proteins, rather than via indirect effects by altering membrane properties. Also, inhibition of copper transport may be a novel effect of xenon that contributes to anesthesia.
Highlights
There has been substantial interest in using noble gases as ’ideal’ general anesthetics for more than half a century [1,2]
The choice to utilize the gain-of-function mutant mechano-sensitive channel of large conductance (MscL)-G22E instead of the wild-type MscL was based on the observation that MscL-G22E is spontaneously active in non-stretched membranes while retaining its mechanosensitivity, resulting in a greater open probability [42]
We examined the effect of xenon on the MscL-G22E channel under increased hydrostatic pressure, which has previously been shown to increase the open-probability of this channel [37]
Summary
There has been substantial interest in using noble gases as ’ideal’ general anesthetics for more than half a century [1,2]. Noble gases are useful as a tool in biophysical studies of properties of biological membranes and their protein constituents. Noble gases have preferential affinity for the hydrophobic environment, which provides an opportunity to directly manipulate the functioning of phospholipid membranes [3,4,5]. The effectiveness of volatile anesthetics follows the Meyer-Overton rule [6,7], which states that a greater solubility in olive oil is correlated to a greater anesthetic potency [8].
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