Researchers at Weill Cornell Medicine and Birkbeck, University of London, have identified the binding site where the general anesthetic sevoflurane acts on sodium ion channels, offering an atomic-level view of a process central to anesthesia.
The study, published June 19 in Nature Communications, found that sevoflurane settles into a pocket near the channel's pore-forming region and stabilizes the channel in an inactive state, preventing the electrical signaling nerve cells use to communicate.
General anesthetics have been used for more than 170 years, but researchers still do not fully understand how they produce unconsciousness or why patients can respond differently. Sodium channels are among several types of proteins believed to be affected.
The team used X-ray crystallography to study a bacterial sodium channel from Magnetococcus marinus. The simpler channel retains key features of human sodium channels and allowed researchers to see how the anesthetic interacted with the protein.
Researchers also altered a single amino acid in the binding pocket. That change reduced both sevoflurane binding and its effect on the channel, supporting the conclusion that the pocket plays a direct role in the anesthetic's action.
The work could help scientists design anesthetics that target specific channels more precisely, potentially reducing side effects and improving safety. The findings may also help explain why anesthetic doses and responses vary among patients.
The research team included senior authors Hugh Hemmings of Weill Cornell Medicine and Bonnie Wallace of Birkbeck, along with co-first authors Karl Herold and David Hollingworth. The work received support from the National Institutes of Health, the British Journal of Anaesthesia and Rosetrees Trust.
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