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Wang Y , Yang E , Wells MM , Bondarenko V , Woll K , Carnevale V , Granata D , Klein ML , Eckenhoff RG , Dailey WP , Covarrubias M , Tang P , Xu Y
Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites
J Gen Physiol. 2018 Sep 3;150(9) :1317-1331
PMID: 30018039    PMCID: PMC6122922    URL: https://www.ncbi.nlm.nih.gov/pubmed/30018039
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Voltage-gated sodium (NaV) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic NaV 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 (19)F-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 NaV channels.
1540-7748 Wang, Yali Yang, Elaine ORCID: http://orcid.org/0000-0001-5158-9909 Wells, Marta M Bondarenko, Vasyl Woll, Kellie Carnevale, Vincenzo ORCID: http://orcid.org/0000-0002-1918-8280 Granata, Daniele Klein, Michael L Eckenhoff, Roderic G Dailey, William P ORCID: http://orcid.org/0000-0002-5554-6698 Covarrubias, Manuel ORCID: http://orcid.org/0000-0002-0881-4143 Tang, Pei Xu, Yan ORCID: http://orcid.org/0000-0003-2773-8024 Journal Article United States J Gen Physiol. 2018 Jul 17. pii: jgp.201811993. doi: 10.1085/jgp.201811993.