Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC
Abstract
Pentameric ligand-gated ion channels (pLGICs) are targets of general anesthetics, but molecular mechanisms underlying anesthetic action remain debatable. We found that ELIC, a pLGIC from Erwinia chrysanthemi, can be functionally inhibited by isoflurane and other anesthetics. Structures of ELIC co-crystallized with isoflurane in the absence or presence of an agonist revealed double isoflurane occupancies inside the pore near T237(6') and A244(13'). A pore-radius contraction near the extracellular entrance was observed upon isoflurane binding. Electrophysiology measurements with a single-point mutation at position 6' or 13' support the notion that binding at these sites renders isoflurane inhibition. Molecular dynamics simulations suggested that isoflurane binding was more stable in the resting than in a desensitized pore conformation. This study presents compelling evidence for a direct pore-binding mechanism of isoflurane inhibition, which has a general implication for inhibitory action of general anesthetics on pLGICs.
- Authors:
-
- Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Anesthesiology
- Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Anesthesiology; Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Pharmacology and Chemical Biology
- Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Anesthesiology; Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Computational and Systems Biology
- SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
- Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Anesthesiology; Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Pharmacology and Chemical Biology; Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Structural Biology
- Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Anesthesiology; Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Pharmacology and Chemical Biology; Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States). Dept. of Computational and Systems Biology
- Publication Date:
- Research Org.:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1624795
- Grant/Contract Number:
- AC02-76SF00515; T32GM075770; T32EB009403; P41GM103393; TG-MCB050030N; 01GM056257; R01GM066358
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Scientific Reports
- Additional Journal Information:
- Journal Volume: 5; Journal Issue: 1; Journal ID: ISSN 2045-2322
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; Computational biophysics; Permeation and transport; X-ray crystallography
Citation Formats
Chen, Qiang, Kinde, Monica N., Arjunan, Palaniappa, Wells, Marta M., Cohen, Aina E., Xu, Yan, and Tang, Pei. Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC. United States: N. p., 2015.
Web. doi:10.1038/srep13833.
Chen, Qiang, Kinde, Monica N., Arjunan, Palaniappa, Wells, Marta M., Cohen, Aina E., Xu, Yan, & Tang, Pei. Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC. United States. https://doi.org/10.1038/srep13833
Chen, Qiang, Kinde, Monica N., Arjunan, Palaniappa, Wells, Marta M., Cohen, Aina E., Xu, Yan, and Tang, Pei. Tue .
"Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC". United States. https://doi.org/10.1038/srep13833. https://www.osti.gov/servlets/purl/1624795.
@article{osti_1624795,
title = {Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC},
author = {Chen, Qiang and Kinde, Monica N. and Arjunan, Palaniappa and Wells, Marta M. and Cohen, Aina E. and Xu, Yan and Tang, Pei},
abstractNote = {Pentameric ligand-gated ion channels (pLGICs) are targets of general anesthetics, but molecular mechanisms underlying anesthetic action remain debatable. We found that ELIC, a pLGIC from Erwinia chrysanthemi, can be functionally inhibited by isoflurane and other anesthetics. Structures of ELIC co-crystallized with isoflurane in the absence or presence of an agonist revealed double isoflurane occupancies inside the pore near T237(6') and A244(13'). A pore-radius contraction near the extracellular entrance was observed upon isoflurane binding. Electrophysiology measurements with a single-point mutation at position 6' or 13' support the notion that binding at these sites renders isoflurane inhibition. Molecular dynamics simulations suggested that isoflurane binding was more stable in the resting than in a desensitized pore conformation. This study presents compelling evidence for a direct pore-binding mechanism of isoflurane inhibition, which has a general implication for inhibitory action of general anesthetics on pLGICs.},
doi = {10.1038/srep13833},
journal = {Scientific Reports},
number = 1,
volume = 5,
place = {United States},
year = {Tue Sep 08 00:00:00 EDT 2015},
month = {Tue Sep 08 00:00:00 EDT 2015}
}
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Structural Basis for Xenon Inhibition in a Cationic Pentameric Ligand-Gated Ion Channel
journal, February 2016
- Sauguet, Ludovic; Fourati, Zeineb; Prangé, Thierry
- PLOS ONE, Vol. 11, Issue 2
Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors
journal, July 2016
- Burgos, Carlos F.; Yévenes, Gonzalo E.; Aguayo, Luis G.
- Molecular Pharmacology, Vol. 90, Issue 3
Structural Studies of GABAA Receptor Binding Sites: Which Experimental Structure Tells us What?
journal, June 2016
- Puthenkalam, Roshan; Hieckel, Marcel; Simeone, Xenia
- Frontiers in Molecular Neuroscience, Vol. 9
Recent progress on the molecular pharmacology of propofol
journal, January 2018
- Tang, Pei; Eckenhoff, Roderic
- F1000Research, Vol. 7
Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels
journal, April 2018
- Fourati, Zaineb; Howard, Rebecca J.; Heusser, Stephanie A.
- Cell Reports, Vol. 23, Issue 4
Structural Studies of GABAA Receptor Binding Sites: Which Experimental Structure Tells us What?
journal, June 2016
- Puthenkalam, Roshan; Hieckel, Marcel; Simeone, Xenia
- Frontiers in Molecular Neuroscience, Vol. 9