Evidence map›Paper›PMID 25827497›Full record

ArticleNeuroscience2015

Manipulations of extracellular Loop 2 in α1 GlyR ultra-sensitive ethanol receptors (USERs) enhance receptor sensitivity to isoflurane, ethanol, and lidocaine, but not propofol.

A Naito, K H Muchhala, J Trang, L Asatryan, J R Trudell, G E Homanics, R L Alkana, D L Davies

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
0.3field-weighted citation impact, top 38% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 7 citations in OpenAlex.

  1. Review
  2. [Inhalational anesthetics].Der Anaesthesist · 2021
    Article
  3. Review
  4. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 3 institutions in 1 country.

A NaitoDepartment of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
K H MuchhalaDepartment of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
J TrangDepartment of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
L AsatryanTitus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
J R TrudellDepartment of Anesthesia, Beckman Program for Molecular and Genetic Medicine, Stanford University, Stanford University Medical Center, Stanford, CA 94305, USA.
G E HomanicsDepartment of Anesthesiology, University of Pittsburgh, 6060 Biomedical Science Tower 3, Pittsburgh, PA 15261, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, 6060 Biomedical Science Tower 3, Pittsburgh, PA 15261, USA.
R L AlkanaDepartment of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
D L DaviesTitus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90089, USA. Electronic address: ddavies@usc.edu.
University of Southern California · USStanford Medicine · USUniversity of Pittsburgh · US

Funding

Ethanol Mechanisms in GABAAR Gene Targeted MiceR37AA010422 · NIAAA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HOMANICS, GREGG E. · 2010 to 2019
$4.4M
ETHANOL MECHANISMS IN GABAAR GENE TARGETED MICER01AA010422 · NIAAA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI HOMANICS, GREGG E. · 1995 to 2008
$3.1M
Regulation of Alcohol Intake by Purinergic P2X4 ReceptorsR01AA022448 · NIAAA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI DAVIES, DARYL L · 2013 to 2020
$2.9M
Defining Alcohol Binding Sites in Ligand-Gated Ion ChannelsR01AA020980 · NIAAA · STANFORD UNIVERSITY · PI BERTACCINI, EDWARD J · 2013 to 2017
$1.6M
Sites of Ethanol Action in Purinergic P2X4 ReceptorsK01AA017243 · NIAAA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ASATRYAN, LIANA · 2008 to 2011
$484k
NIAAA NIH HHS AA020980NIAAA NIH HHS AA022448NIAAA NIH HHS AA10422NIAAA NIH HHS AA17243NIAAA NIH HHS R01 AA010422NIAAA NIH HHS R01 AA020980NIAAA NIH HHS R01 AA022448NIAAA NIH HHS R37 AA010422
6 · The paper itself

Abstract

We recently developed ultra-sensitive ethanol receptors (USERs) as a novel tool for investigation of single receptor subunit populations sensitized to extremely low ethanol concentrations that do not affect other receptors in the nervous system. To this end, we found that mutations within the extracellular Loop 2 region of glycine receptors (GlyRs) and γ-aminobutyric acid type A receptors (GABAARs) can significantly increase receptor sensitivity to micro-molar concentrations of ethanol resulting in up to a 100-fold increase in ethanol sensitivity relative to wild-type (WT) receptors. The current study investigated: (1) Whether structural manipulations of Loop 2 in α1 GlyRs could similarly increase receptor sensitivity to other anesthetics; and (2) If mutations exclusive to the C-terminal end of Loop 2 are sufficient to impart these changes. We expressed α1 GlyR USERs in Xenopus oocytes and tested the effects of three classes of anesthetics, isoflurane (volatile), propofol (intravenous), and lidocaine (local), known to enhance glycine-induced chloride currents using two-electrode voltage clamp electrophysiology. Loop 2 mutations produced a significant 10-fold increase in isoflurane and lidocaine sensitivity, but no increase in propofol sensitivity compared to WT α1 GlyRs. Interestingly, we also found that structural manipulations in the C-terminal end of Loop 2 were sufficient and selective for α1 GlyR modulation by ethanol, isoflurane, and lidocaine. These studies are the first to report the extracellular region of α1 GlyRs as a site of lidocaine action. Overall, the findings suggest that Loop 2 of α1 GlyRs is a key region that mediates isoflurane and lidocaine modulation. Moreover, the results identify important amino acids in Loop 2 that regulate isoflurane, lidocaine, and ethanol action. Collectively, these data indicate the commonality of the sites for isoflurane, lidocaine, and ethanol action, and the structural requirements for allosteric modulation on α1 GlyRs within the extracellular Loop 2 region.

Indexed as

AnimalsBiophysicsCentral Nervous System DepressantsDose-Response Relationship, DrugElectric StimulationEthanolExtracellular SpaceHypnotics and SedativesIsofluraneLidocaineMembrane PotentialsMutationOocytesPatch-Clamp TechniquesPropofolReceptors, GlycineCentral Nervous System DepressantsEthanolHypnotics and SedativesIsofluraneLidocainePropofolReceptors, Glycineethanolisofluranelidocaineligand-gated ion channelLoop 2α1 GlyRs

Identifiers

PMID25827497
PMCPMC4428915
OpenAlexW1995756891

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.