Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites.

Authors

Yali Wang, University of Pittsburgh School of Medicine
Elaine Yang, Thomas Jefferson UniversityFollow
Marta M. Wells, University of Pittsburgh School of Medicine
Vasyl Bondarenko, University of Pittsburgh School of Medicine
Kellie Woll, Lincoln University of Pennsylvania
Vincenzo Carnevale, Temple University
Daniele Granata, Temple University
Michael L. Klein, Temple University
Roderic G. Eckenhoff, University of Pennsylvania
William P. Dailey, University of Pennsylvania
Manuel Covarrubias, Thomas Jefferson UniversityFollow
Pei Tang, University of Pittsburgh School of Medicine
Yan Xu, University of Pittsburgh School of Medicine

Document Type

Article

Publication Date

9-1-2018

Comments

This article has been peer reviewed. It is the author’s final published version in Journal of General Physiology, Volume 150, Issue 9, September 2018, Pages 1317-1332.

The published version is available at https://doi.org/10.1085/jgp.201811993. Copyright © Wang et al.

Abstract

Voltage-gated sodium (Na_V) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic Na_V channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac. We then strategically place small fluorinated probes at these putative binding sites and experimentally quantify the interaction strengths with a fluorinated propofol analogue, 4-fluoropropofol. In vitro and in vivo measurements show that 4-fluoropropofol and propofol have similar effects on NaChBac function and nearly identical anesthetizing effects on tadpole mobility. Using quantitative analysis by ¹⁹F-NMR saturation transfer difference spectroscopy, we reveal strong intermolecular cross-relaxation rate constants between 4-fluoropropofol and four different regions of NaChBac, including the activation gate and selectivity filter in the pore, the voltage sensing domain, and the S4-S5 linker. Unlike volatile anesthetics, 4-fluoropropofol does not bind to the extracellular interface of the pore domain. Collectively, our results show that propofol inhibits NaChBac at multiple sites, likely with distinct modes of action. This study provides a molecular basis for understanding the net inhibitory action of propofol on Na_V channels. © 2018 Wang et al.

Recommended Citation

Wang, Yali; Yang, Elaine; Wells, Marta M.; Bondarenko, Vasyl; Woll, Kellie; Carnevale, Vincenzo; Granata, Daniele; Klein, Michael L.; Eckenhoff, Roderic G.; Dailey, William P.; Covarrubias, Manuel; Tang, Pei; and Xu, Yan, "Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites." (2018). Department of Neuroscience Faculty Papers. Paper 37.
https://jdc.jefferson.edu/department_neuroscience/37

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Language

English