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Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites.
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; Xu, Yan.
Afiliação
  • Wang Y; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
  • Yang E; Department of Neuroscience and Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College and Jefferson College of Biomedical Sciences, Thomas Jefferson University, Philadelphia, PA.
  • Wells MM; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
  • Bondarenko V; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
  • Woll K; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
  • Carnevale V; Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA.
  • Granata D; Institute for Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, PA.
  • Klein ML; Institute for Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, PA.
  • Eckenhoff RG; Institute for Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, PA.
  • Dailey WP; Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA.
  • Covarrubias M; Department of Chemistry, University of Pennsylvania, Philadelphia, PA.
  • Tang P; Department of Neuroscience and Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College and Jefferson College of Biomedical Sciences, Thomas Jefferson University, Philadelphia, PA.
  • Xu Y; Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
J Gen Physiol ; 150(9): 1317-1331, 2018 09 03.
Article em En | MEDLINE | ID: mdl-30018039
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 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 NaV channels.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Bactérias / Canais de Sódio / Propofol / Hipnóticos e Sedativos Limite: Animals / Humans Idioma: En Revista: J Gen Physiol Ano de publicação: 2018 Tipo de documento: Article País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Bactérias / Canais de Sódio / Propofol / Hipnóticos e Sedativos Limite: Animals / Humans Idioma: En Revista: J Gen Physiol Ano de publicação: 2018 Tipo de documento: Article País de publicação: Estados Unidos