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Research Article

Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to α4/6β3δ GABAA receptors

H. Jacob Hanchar, Panida Chutsrinopkun, Pratap Meera, Porntip Supavilai, Werner Sieghart, Martin Wallner, and Richard W. Olsen
PNAS May 30, 2006 103 (22) 8546-8551; https://doi.org/10.1073/pnas.0509903103
H. Jacob Hanchar
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Panida Chutsrinopkun
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Pratap Meera
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Porntip Supavilai
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Werner Sieghart
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Martin Wallner
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  • For correspondence: mwallner@mednet.ucla.edu rolsen@mednet.ucla.edu
Richard W. Olsen
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  • For correspondence: mwallner@mednet.ucla.edu rolsen@mednet.ucla.edu
  1. Edited by Floyd E. Bloom, The Scripps Research Institute, La Jolla, CA, and approved February 10, 2006

  2. ↵ †H.J.H. and P.C. contributed equally to this work. (received for review November 16, 2005)

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  • Alcohol-sensitive GABA receptors and alcohol antagonists
    - May 22, 2006
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Abstract

Although GABAA receptors have long been implicated in mediating ethanol (EtOH) actions, receptors containing the “nonsynaptic” δ subunit only recently have been shown to be uniquely sensitive to EtOH. Here, we show that δ subunit-containing receptors bind the imidazo-benzodiazepines (BZs) flumazenil and Ro15-4513 with high affinity (K d < 10 nM), contrary to the widely held belief that these receptors are insensitive to BZs. In immunopurified native cerebellar and recombinant δ subunit-containing receptors, binding of the alcohol antagonist [3H]Ro15-4513 is inhibited by low concentrations of EtOH (K i ≈ 8 mM). Also, Ro15-4513 binding is inhibited by BZ-site ligands that have been shown to reverse the behavioral alcohol antagonism of Ro15-4513 (i.e., flumazenil, β-carbolinecarboxylate ethyl ester (β-CCE), and N-methyl-β-carboline-3-carboxamide (FG7142), but not including any classical BZ agonists like diazepam). Experiments that were designed to distinguish between a competitive and allosteric mechanism suggest that EtOH and Ro15-4513 occupy a mutually exclusive binding site. The fact that only Ro15-4513, but not flumazenil, can inhibit the EtOH effect, and that Ro15-4513 differs from flumazenil by only a single group in the molecule (an azido group at the C7 position of the BZ ring) suggest that this azido group in Ro15-4513 might be the area that overlaps with the alcohol-binding site. Our findings, combined with previous observations that Ro15-4513 is a behavioral alcohol antagonist, suggest that many of the behavioral effects of EtOH at relevant physiological concentrations are mediated by EtOH/Ro15-4513-sensitive GABAA receptors.

  • alcohol receptor
  • flumazenil
  • β-carbolines
  • extrasynaptic GABAA receptors

Footnotes

  • ‖To whom correspondence may be addressed at:
    Department of Molecular and Medical Pharmacology, University of California, Room 23-120 CHS, Charles Young Drive South, Los Angeles, CA 90095-1735.
    E-mail: mwallner{at}mednet.ucla.edu or rolsen{at}mednet.ucla.edu
  • See Commentary on page 8307.

  • Author contributions: H.J.H., M.W., and R.W.O. designed research; H.J.H., P.C., P.M., and M.W. performed research; P.S. and W.S. contributed new reagents/analytic tools; H.J.H., P.C., M.W., and R.W.O. analyzed data; and W.S., M.W., and R.W.O. wrote the paper.

  • Conflict of interest statement: M.W., R.W.O., and H.J.H. have filed a U.S. Provisional Patent Application, Serial No. 60/693,844.

  • This paper was submitted directly (Track II) to the PNAS office.

  • Abbreviations:

    Abbreviations:

    GABAAR,
    GABAA receptor;
    HEK,
    human embryonic kidney;
    BZ,
    benzodiazepine;
    EtOH,
    ethanol;
    IP,
    immunoprecipitated/immunoprecipitation;
    β-CCE,
    β-carboline-3-carboxyethyl ester;
    DMCM,
    methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate;
    DZ,
    diazepam;
    DZ-IS,
    DZ-insensitive;
    FG7142,
    N-methyl-β-carboline-3-carboxamide.
  • © 2006 by The National Academy of Sciences of the USA
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Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to α4/6β3δ GABAA receptors
H. Jacob Hanchar, Panida Chutsrinopkun, Pratap Meera, Porntip Supavilai, Werner Sieghart, Martin Wallner, Richard W. Olsen
Proceedings of the National Academy of Sciences May 2006, 103 (22) 8546-8551; DOI: 10.1073/pnas.0509903103

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Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to α4/6β3δ GABAA receptors
H. Jacob Hanchar, Panida Chutsrinopkun, Pratap Meera, Porntip Supavilai, Werner Sieghart, Martin Wallner, Richard W. Olsen
Proceedings of the National Academy of Sciences May 2006, 103 (22) 8546-8551; DOI: 10.1073/pnas.0509903103
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