The propofol binding sites of prokaryotic voltage-gated sodium channels
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Abstract
Propofol, one of the most commonly used intravenous general anesthetics, modulates neuronal function by interacting with ion channels. The mechanisms that link propofol binding to the modulation of distinct ion channel states, however, are not understood. To tackle this problem, we investigated prokaryotic ancestors of eukaryotic voltage-gated Na + channels (Navs) using unbiased photoaffinity labeling with a photoacitivatable propofol analog (AziP m ), electrophysiological methods and mutagenesis. The results directly demonstrate conserved propofol binding sites involving the S4 voltage sensors and the S4-S5 linkers in NaChBac and NavMs, and also suggest state-dependent changes at these sites. Then, using molecular dynamics simulations to elucidate the structural basis of propofol modulation, we show that the S4 voltage sensors and the S4-S5 linkers shape two distinct propofol binding sites in a conformation-dependent manner. These interactions help explain how propofol binding promotes activation-coupled inactivation to inhibit Nav channel function.
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Summary: This research makes important, incremental contributions to the fundamental understanding of propofol interactions with bacterial voltage-gated sodium channels.
Public Review:
The reviewers agree that this research adds to the fundamental understanding of propofol interactions with bacterial voltage-gated sodium channels. Here an objective avenue to binding site mapping is taken involving a photoactivated azide propofol derivative. The strategy identifies two adjacent sites at the intracellular face of Nav channels. These sites are provocative as they settle into a mechanistically rich channel region where the voltage-sensor is coupled to the pore. The manuscript is well-written and referenced, and the conclusions are aligned with the data presented. The methods are appropriate, the data appear to be of high quality. The …
Summary: This research makes important, incremental contributions to the fundamental understanding of propofol interactions with bacterial voltage-gated sodium channels.
Public Review:
The reviewers agree that this research adds to the fundamental understanding of propofol interactions with bacterial voltage-gated sodium channels. Here an objective avenue to binding site mapping is taken involving a photoactivated azide propofol derivative. The strategy identifies two adjacent sites at the intracellular face of Nav channels. These sites are provocative as they settle into a mechanistically rich channel region where the voltage-sensor is coupled to the pore. The manuscript is well-written and referenced, and the conclusions are aligned with the data presented. The methods are appropriate, the data appear to be of high quality. The manuscript is internally consistent and well written. The findings are quite interesting.
The primary concern is that these results were deemed to add incrementally to recently published studies (Yang et al., JGP, 2018) which came to similar conclusions, without the support of the photoaffinity ligand results. Additionally, there were questions about whether voltage-gated sodium channels are involved in the anesthetic actions of propofol, technical questions about molecular simulations, and suggestions for control experiments.
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