Journal article
Fluorine-19 NMR and computational quantification of isoflurane binding to the voltage-gated sodium channel NaChBac
Proceedings of the National Academy of Sciences - PNAS, v 113(48), pp 13762-13767
29 Nov 2016
PMID: 27856739
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Voltage-gated sodium channels (Na
) play an important role in general anesthesia. Electrophysiology measurements suggest that volatile anesthetics such as isoflurane inhibit Na
by stabilizing the inactivated state or altering the inactivation kinetics. Recent computational studies suggested the existence of multiple isoflurane binding sites in Na
, but experimental binding data are lacking. Here we use site-directed placement of
F probes in NMR experiments to quantify isoflurane binding to the bacterial voltage-gated sodium channel NaChBac.
F probes were introduced individually to S129 and L150 near the S4-S5 linker, L179 and S208 at the extracellular surface, T189 in the ion selectivity filter, and all phenylalanine residues. Quantitative analyses of
F NMR saturation transfer difference (STD) spectroscopy showed a strong interaction of isoflurane with S129, T189, and S208; relatively weakly with L150; and almost undetectable with L179 and phenylalanine residues. An orientation preference was observed for isoflurane bound to T189 and S208, but not to S129 and L150. We conclude that isoflurane inhibits NaChBac by two distinct mechanisms: (i) as a channel blocker at the base of the selectivity filter, and (ii) as a modulator to restrict the pivot motion at the S4-S5 linker and at a critical hinge that controls the gating and inactivation motion of S6.
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Details
- Title
- Fluorine-19 NMR and computational quantification of isoflurane binding to the voltage-gated sodium channel NaChBac
- Creators
- Monica N Kinde - University of PittsburghVasyl Bondarenko - University of PittsburghDaniele Granata - Temple UniversityWeiming Bu - University of PennsylvaniaKimberly C Grasty - Drexel UniversityPatrick J Loll - Drexel UniversityVincenzo Carnevale - Temple UniversityMichael L Klein - Temple UniversityRoderic G Eckenhoff - University of PennsylvaniaPei Tang - University of PittsburghYan Xu - University of Pittsburgh
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 113(48), pp 13762-13767
- Publisher
- PNAS
- Grant note
- T32 GM075770 / NIGMS NIH HHS R37 GM049202 / NIGMS NIH HHS R01 GM049202 / NIGMS NIH HHS P01 GM055876 / NIGMS NIH HHS R56 GM056257 / NIGMS NIH HHS R01 GM056257 / NIGMS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000388835700069
- Scopus ID
- 2-s2.0-84999115993
- Other Identifier
- 991019168610404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Multidisciplinary Sciences