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Title: Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to α4/6β3δ GABAA receptors
Authors: H. Jacob Hanchar
Panida Chutsrinopkun
Pratap Meera
Porntip Supavilai
Werner Sieghart
Martin Wallner
Richard W. Olsen
University of California, Los Angeles
Mahidol University
Medizinische Universitat Wien
Keywords: Biochemistry, Genetics and Molecular Biology;Multidisciplinary
Issue Date: 30-May-2006
Citation: Proceedings of the National Academy of Sciences of the United States of America. Vol.103, No.22 (2006), 8546-8551
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 (Kd < 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 GABA A receptors. © 2006 by The National Academy of Sciences of the USA.
ISSN: 00278424
Appears in Collections:Scopus 2006-2010

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