The article investigates the structural basis and mechanism of propofol inhibition of HCN1 channels, which are essential for pacemaking activity and neural signaling. Using single-particle cryo-electron microscopy and electrophysiology, the researchers found that propofol binds to a groove between the S5 and S6 transmembrane helices of the HCN1 channel.
Importantly, the study shows that propofol can restore voltage-dependent closing in two HCN1 epilepsy-associated mutations, M305L and D401H, which act by destabilizing the channel's closed state. By tracking voltage-sensor movement in spHCN channels, the authors determined that propofol inhibition is independent of voltage-sensor conformational changes, suggesting that voltage-dependent closure requires the integrity of the methionine-phenylalanine interface in the S5-S6 region.
The findings provide a structural and mechanistic understanding of how propofol inhibits HCN1 channels and how it can rescue voltage-dependent gating in certain epilepsy-associated mutations. This knowledge could help in the design of specific drugs targeting HCN channelopathies.
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