New research led by the Perelman School of Medicine at the University of Pennsylvania has found that sevoflurane binding at multiple key cell membrane protein locations may contribute to the induction of the anaesthetic response.
Previous studies have suggested that inhaled general anaesthetics such as sevoflurane might work by inactivating sodium channels. However, despite the physiological importance of sodium channels and their possible role as general anaesthetic targets, little is known about interaction sites or the mechanism of action.
A team led by Roderic Eckenhoff, vice chair for Research and the Austin Lamont Professor of Anesthesiology and Critical Care at Penn, found that sevoflurane’s interaction with sodium channels plays an essential role in the generation of the electrical impulses necessary for communication between nerve cells in the brain. “We sought to understand the molecular basis of the interaction of sevoflurane with the sodium channel as a starting point to determine how similar anaesthetics might elicit the anaesthetic response,” said Annika Barber, a post-doc at the Perelman School of Medicine.
Barber used molecular dynamic simulation to visualise possible interactions of sevoflurane with discrete parts of the bacterial sodium channel NaChBac. This archetypal membrane protein is homologous with sodium channels found in the human brain. “Given the physical and chemical properties of inhaled anaesthetics, we expected binding to many possible sites; simulation helped us limit and identify the sites where the binding of sevoflurane might actually change the function of the sodium channel,” explained Barber.
The team found three key binding sites possibly linked to the anaesthetic response: the sodium pore itself; the gate that governs opening and closing of the sodium channel in response to a voltage change across the membrane of a neuron; and a second gate that controls sodium flow by changing the shape of the channel’s narrow pore. It is thought that the three sites work together to turn off firing of electrical impulses in key neurons, and thus induce the anaesthetic state.
The functional significance of these sites was validated by directly measuring the activity of the sodium channel and conducting additional computer simulations. They found that low doses of sevoflurane made voltage-dependent activation of the sodium channel more favourable. This surprising action could explain the excitatory phase many patients experience during the onset of sevoflurane anaesthesia. However, as concentrations of the anaesthetic increase, sevoflurane begins to block the sodium channel, which might ultimately contribute to the state of anaesthesia. These dose-dependent, mutually antagonistic effects, in a single ion channel were surprising to the group, emphasise the complexity of anesthetic action and pave the way for future research.
