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Research ArticleNeuropharmacology

Characterization of Two Mutations, M287L and Q266I, in the α1 Glycine Receptor Subunit That Modify Sensitivity to Alcohols

Cecilia M. Borghese, Yuri A. Blednov, Yu Quan, Sangeetha V. Iyer, Wei Xiong, S. John Mihic, Li Zhang, David M. Lovinger, James R. Trudell, Gregg E. Homanics and R. Adron Harris
Journal of Pharmacology and Experimental Therapeutics February 2012, 340 (2) 304-316; DOI: https://doi.org/10.1124/jpet.111.185116
Cecilia M. Borghese
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Yuri A. Blednov
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Yu Quan
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Sangeetha V. Iyer
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Wei Xiong
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S. John Mihic
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Li Zhang
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David M. Lovinger
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James R. Trudell
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Gregg E. Homanics
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R. Adron Harris
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Abstract

Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels. Ethanol potentiates glycine activation of the GlyR, and putative binding sites for alcohol are located in the transmembrane (TM) domains between and within subunits. To alter alcohol sensitivity of GlyR, we introduced two mutations in the GlyR α1 subunit, M287L (TM3) and Q266I (TM2). After expression in Xenopus laevis oocytes, both mutants showed a reduction in glycine sensitivity and glycine-induced maximal currents. Activation by taurine, another endogenous agonist, was almost abolished in the M287L GlyR. The ethanol potentiation of glycine currents was reduced in the M287L GlyR and eliminated in Q266I. Physiological levels of zinc (100 nM) potentiate glycine responses in wild-type GlyR and also enhance the ethanol potentiation of glycine responses. Although zinc potentiation of glycine responses was unchanged in both mutants, zinc enhancement of ethanol potentiation of glycine responses was absent in M287L GlyRs. The Q266I mutation decreased conductance but increased mean open time (effects not seen in M287L). Two lines of knockin mice bearing these mutations were developed. Survival of homozygous knockin mice was impaired, probably as a consequence of impaired glycinergic transmission. Glycine showed a decreased capacity for displacing strychnine binding in heterozygous knockin mice. Electrophysiology in isolated neurons of brain stem showed decreased glycine-mediated currents and decreased ethanol potentiation in homozygous knockin mice. Molecular models of the wild-type and mutant GlyRs show a smaller water-filled cavity within the TM domains of the Q266I α1 subunit. The behavioral characterization of these knockin mice is presented in a companion article (J Pharmacol Exp Ther 340:317–329, 2012).

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Alcohol Abuse and Alcoholism [Grants AA06399, AA11525, AA10422]; and the National Institutes of Health National Institute of General Medical Sciences [Grant GM47818].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.185116.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    GlyR
    glycine receptor
    TM
    transmembrane
    WT
    wild type
    HEK
    human embryonic kidney
    ES
    embryonic stem
    ANOVA
    analysis of variance
    PCR
    polymerase chain reaction
    GLIC
    proton-gated ion channel
    CRC
    concentration-response curve
    bp
    base pairs
    kb
    kilobases
    aCSF
    artificial cerebrospinal fluid
    MBS
    Modified Barth's solution.

  • Received August 10, 2011.
  • Accepted October 27, 2011.
  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 340 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 2
1 Feb 2012
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Research ArticleNeuropharmacology

M287L and Q266I Mutations in α1 GlyR and Alcohol

Cecilia M. Borghese, Yuri A. Blednov, Yu Quan, Sangeetha V. Iyer, Wei Xiong, S. John Mihic, Li Zhang, David M. Lovinger, James R. Trudell, Gregg E. Homanics and R. Adron Harris
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 304-316; DOI: https://doi.org/10.1124/jpet.111.185116

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Research ArticleNeuropharmacology

M287L and Q266I Mutations in α1 GlyR and Alcohol

Cecilia M. Borghese, Yuri A. Blednov, Yu Quan, Sangeetha V. Iyer, Wei Xiong, S. John Mihic, Li Zhang, David M. Lovinger, James R. Trudell, Gregg E. Homanics and R. Adron Harris
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 304-316; DOI: https://doi.org/10.1124/jpet.111.185116
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