Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC

Chen, Qiang; Kinde, Monica N.; Arjunan, Palaniappa; Wells, Marta M.; Cohen, Aina E.; Xu, Yan; Tang, Pei

doi:10.1038/srep13833

Title: Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC

Journal Article · Tue Sep 08 00:00:00 EDT 2015 · Scientific Reports

DOI:https://doi.org/10.1038/srep13833· OSTI ID:1624795

Chen, Qiang ^[1]; Kinde, Monica N. ^[1]; Arjunan, Palaniappa ^[2]; Wells, Marta M. ^[3]; Cohen, Aina E. ^[4]; Xu, Yan ^[5]; Tang, Pei ^[6]

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

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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515; T32GM075770; T32EB009403; P41GM103393; TG-MCB050030N; 01GM056257; R01GM066358

OSTI ID:: 1624795

Journal Information:: Scientific Reports, Vol. 5, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 25 works

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Title: Direct Pore Binding as a Mechanism for Isoflurane Inhibition of the Pentameric Ligand-gated Ion Channel ELIC

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