Journal article
Binding Sites and the Mechanism of Action of Propofol and a Photoreactive Analogue in Prokaryotic Voltage-Gated Sodium Channels
ACS chemical neuroscience, v 12(20), pp 3898-3914
20 Oct 2021
PMID: 34607428
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 the prokaryotic ancestors of eukaryotic voltage-gated Na+ channels (Nays) using unbiased photoaffinity labeling (PAL) with a diazirine derivative of propofol (AziPm), electrophysiological methods, and mutagenesis. AziPm inhibits Nav function in a manner that is indistinguishable from that of the parent compound by promoting activation-coupled inactivation. In several replicates (8/9) involving NaChBac and NavMs, we found adducts at residues located at the C-terminal end of the S4 voltage sensor, the S4-S5 linker, and the N-terminal end of the S5 segment. However, the non-inactivating mutant NaChBac-T220A yielded adducts that were different from those found in the wild-type counterpart, which suggested state-dependent changes at the binding site. Then, using molecular dynamics simulations to further elucidate the structural basis of Nay modulation by propofol, we show that the S4 voltage sensors and the S4-S5 linkers shape two distinct propofol binding sites in a conformation-dependent manner. Supporting the PAL and MD simulation results, we also found that Ala mutations of a subset of adducted residues have distinct effects on gating modulation of NaChBac and NavMs by propofol. The results of this study provide direct insights into the structural basis of the mechanism through which propofol binding promotes activation-coupled inactivation to inhibit Nay channel function.
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Details
- Title
- Binding Sites and the Mechanism of Action of Propofol and a Photoreactive Analogue in Prokaryotic Voltage-Gated Sodium Channels
- Creators
- Elaine Yang - Thomas Jefferson UniversityWeiming Bu - University of PennsylvaniaAntonio Suma - INFN Sezione di BariVincenzo Carnevale - Temple UniversityKimberly C. Grasty - Drexel UniversityPatrick J. Loll - Drexel UniversityKellie Woll - University of PennsylvaniaNatarajan Bhanu - University of PennsylvaniaBenjamin A. Garcia - University of PennsylvaniaRoderic G. Eckenhoff - University of PennsylvaniaManuel Covarrubias - Thomas Jefferson University
- Publication Details
- ACS chemical neuroscience, v 12(20), pp 3898-3914
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 17
- Grant note
- P01GM55876; 1R01NS111997-01A1; F30GM123612 / National Institutes of Health, USA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000710926100011
- Scopus ID
- 2-s2.0-85117248098
- Other Identifier
- 991019168449704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Medicinal
- Neurosciences