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. The findings were published June 19 in Nature Communications. 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.
For 175 years, doctors have safely used inhaled anesthetics to render patients unconscious but did not 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," he said.
The study provides what researchers describe as the first atomic-level view of how sevoflurane binds to sodium channels and stabilizes them in an inactive state. Scientists had suspected since the 1970s that inhaled volatile anesthetics could interact with ion channels—particularly voltage-gated sodium channels—but detailed structural analysis was difficult due to the complexity of mammalian sodium channels.
To address this challenge, researchers turned to Magnetococcus marinus, a marine bacterium with structurally simpler voltage-gated sodium channels similar in function and sensitivity to those found in mammals. "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." The team collaborated with UK-based experts Dr. Bonnie Ann Wallace and David Hollingworth from Birkbeck.
Using high-resolution X-ray crystallography, they captured detailed images showing sevoflurane tucked into a pocket at the edge of the channel's pore-forming region—away from where sodium ions flow—which stabilizes it in an inactive state and reduces neuronal signaling capability. Altering a single amino acid in this pocket prevented effective binding by sevoflurane.
The researchers now aim to translate their findings from bacteria back into mammalian systems for further understanding human responses to anesthesia. "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." He added, "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."
