期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 22, 页码 8546-8551出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0509903103
关键词
alcohol receptor; flumazenil; beta-carbolines; extrasynaptic GABA(A) receptors
资金
- NIAAA NIH HHS [F31 AA015460, R37 AA007680, AA 07680, AA 015460, R01 AA007680] Funding Source: Medline
- NINDS NIH HHS [P01 NS035985, NS 35985] Funding Source: Medline
Although GABA(A) receptors have long been implicated in mediating ethanol (EtOH) actions, receptors containing the nonsynaptic delta subunit only recently have been shown to be uniquely sensitive to EtOH. Here, we show that delta 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 6 subunit-containing receptors, binding of the alcohol antagonist [H-3]Ro15-4513 is inhibited by low concentrations of EtOH (K-i approximate to 8 mM). Also, Ro15-45113 binding is inhibited by BZ-site ligands that have been shown to reverse the behavioral alcohol antagonism of Ro15-45113 (i.e., flumazenil, beta-carbolinecarboxylate ethyl ester (beta-CCE), and N-methyl-beta-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 V position of the BZ ring) suggest that this azido group in Ro15-45113 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.
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