Inhaled anaesthetics have been used safely for 175 years, yet exactly how they extinguish consciousness has never been fully explained. A study in Nature Communications, co-led by Hugh Hemmings of Weill Cornell Medicine and Bonnie Ann Wallace of Birkbeck, University of London, supplies a key piece of the answer: the first atomic-level view of where the common anaesthetic sevoflurane binds to voltage-gated sodium channels, the proteins that let neurons fire.
Using high-resolution X-ray crystallography on a sodium channel from the marine bacterium Magnetococcus marinus, which is structurally simpler than mammalian channels but shares their sensitivity to anaesthetics, the team found that sevoflurane lodges in a small pocket at the edge of the pore-forming region, away from the path sodium ions travel. Binding there stabilises the channel in an inactive state, making it less likely to open and so dampening the neuron's ability to transmit signals.
The interaction appears central to the drug's action: changing a single amino acid in the pocket stopped sevoflurane binding effectively and abolished its inactivating effect. The researchers, funded by the National Institutes of Health among others, now plan to test the findings in mammalian systems. Mapping such binding sites could guide the design of safer, more selective anaesthetics, and naturally occurring variants in the pocket may help explain why patients respond differently to anaesthesia.