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Structure. 2017 Jan 3;25(1):180-187. doi: 10.1016/j.str.2016.11.007. Epub 2016 Dec 1.

Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC.

Author information

1
Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
2
Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA; Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
3
Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
4
Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.
5
Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: ptang@pitt.edu.

Abstract

The structural basis for alcohol modulation of neuronal pentameric ligand-gated ion channels (pLGICs) remains elusive. We determined an inhibitory mechanism of alcohol on the pLGIC Erwinia chrysanthemi (ELIC) through direct binding to the pore. X-ray structures of ELIC co-crystallized with 2-bromoethanol, in both the absence and presence of agonist, reveal 2-bromoethanol binding in the pore near T237(6') and the extracellular domain (ECD) of each subunit at three different locations. Binding to the ECD does not appear to contribute to the inhibitory action of 2-bromoethanol and ethanol as indicated by the same functional responses of wild-type ELIC and mutants. In contrast, the ELIC-α1β3GABAAR chimera, replacing the ELIC transmembrane domain (TMD) with the TMD of α1β3GABAAR, is potentiated by 2-bromoethanol and ethanol. The results suggest a dominant role of the TMD in modulating alcohol effects. The X-ray structures and functional measurements support a pore-blocking mechanism for inhibitory action of short-chain alcohols.

KEYWORDS:

ELIC; alcohols; ethanol; pentameric ligand-gated ion channels; pore blocking

PMID:
27916519
PMCID:
PMC5214846
DOI:
10.1016/j.str.2016.11.007
[Indexed for MEDLINE]
Free PMC Article

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