Researchers at Weill Cornell Medicine and Birkbeck, University of London, have identified a site where a commonly used anesthetic binds to sodium ion channels, revealing a molecular mechanism that may explain how these drugs dampen communication between neurons. Ion channels are proteins that regulate the flow of charged particles across cell membranes, enabling neurons to generate electrical signals. By reducing this signaling, inhaled anesthetics help suppress brain activity, producing unconsciousness and immobility during surgery.
The findings , published June 19 in Nature Communications, shed light on a longstanding mystery: For 175 years, doctors have safely used inhaled anesthetics to render patients unconscious, but didn't fully understand how these drugs work.
"Sodium channels are critical for communication between neurons in the brain, and anesthesia breaks down that communication," said Dr. Hugh Hemmings , senior associate dean for research and chair of the Department of Anesthesiology at Weill Cornell, who co-led the research. "So, there's good reason to believe that the unconsciousness produced by volatile anesthetics is related to their effects on sodium channels."
The study provides the first atomic-level view of how the anesthetic sevoflurane binds to sodium channels and stabilizes them in an inactive state. "The insights we gain from this study may enable us to design safer, more selective anesthetics, with fewer side effects," said Dr. Karl Herold , co-first author and senior research associate at Weill Cornell.
Anesthetizing a Bacterial Counterpart
As far back as the 1970s, scientists suspected that inhaled, volatile anesthetics could interact with ion channels—in particular, the voltage-gated sodium channels that play a crucial role in cell-to-cell communication throughout the nervous system. But determining how this interaction inhibits neuronal activity has been challenging because mammalian sodium channels were too large and complex for detailed structural analysis.
The researchers turned to a marine bacterium, Magnetococcus marinus, that uses voltage-gated sodium channels to swim toward nutrients and oxygen. Although structurally simpler than their mammalian counterparts, the bacterial channels operate similarly and share the same sensitivity to anesthetics. "Volatile anesthetics bind through weak, low-affinity interactions that are very hard to capture structurally," Dr. Herold said. "A bacterial channel that behaves like ours but is small enough to crystallize lets us finally see where sevoflurane sits and how it holds the channel inactive."
Discovering a Binding Pocket
The Weill Cornell team joined forces with Birkbeck researchers, co-senior author Dr. Bonnie Ann Wallace and co-first author David Hollingworth. The UK-based researchers have extensive expertise in structural analysis of these bacterial channels bound to a variety of drugs, including those that affect neuronal activity.
Using high-resolution X-ray crystallography, the researchers captured detailed snapshots of sevoflurane bound to the channel. They discovered that the anesthetic tucks into a small pocket at the edge of the channel's pore-forming region, but away from the pathway through which sodium ions flow. Binding in this pocket stabilizes the channel in an inactive state, making it less likely to open and allow sodium ions through, thereby reducing a neuron's ability to transmit electrical signals.
That interaction appears to be key to the drug's molecular effects. When the researchers altered a single amino acid in the binding pocket, sevoflurane could no longer bind effectively and lost its ability to keep the channel in its inactivated state.
The researchers are now working on translating their findings to the mammalian system. "The bacterial channel is just a testing ground," Dr. Hemmings explained. "If naturally occurring mutations affecting anesthetic binding exist in humans, studying them could help explain why some people respond differently to anesthesia and may provide new insights into the biology of consciousness."
"As anesthesiologists, it's our responsibility to understand how these drugs work, so we can resolve issues when people don't react well to anesthesia," said Dr. Hemmings, who is also anesthesiologist-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Hugh Hemmings .
This research was funded by the National Institutes of Health (grant R01 GM58055), a British Journal of Anaesthesia International Collaborative Grant and a Rosetrees Trust grant (ref: CF2/100001). This work was also supported by the Francis Crick Institute, the MRC Biomedical NMR Centre, which is funded by Cancer Research UK (CC1078), the UK Medical Research Council (CC1078), and the Wellcome Trust (CC1078).
