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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Ethanol enhances α_4β_3δ and α_6β_3δ γ-aminobutyric acid type A receptors at low concentrations known to affect humans
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Ethanol enhances α_4β_3δ and α_6β_3δ γ-aminobutyric acid type A receptors at low concentrations known to affect humans

机译：乙醇在已知会影响人类的低浓度下增强α_4β_3δ和α_6β_3δγ-氨基丁酸A型受体

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摘要

γ-Aminobutyric acid type A receptors (GABARs) have long been implicated in mediating ethanol (EtOH) actions, but so far most of the reported recombinant GABAR combinations have shown EtOH responses only at fairly high concentrations (≥ 60 mM). We show that GABARs containing the δ-subunit, which are highly sensitive to γ-aminobutyric acid, slowly inactivating, and thought to be located outside of synapses, are enhanced by EtOH at concentrations that are reached with moderate, social EtOH consumption. Reproducible ethanol enhancements occur at 3 mM, a concentration six times lower than the legal blood-alcohol intoxication (driving) limit in most states (0.08% wt/vol or 17.4 mM). GABARs responsive to these low EtOH concentrations require the GABAR δ-subunit, which is thought to be associated exclusively with α_4-and α_6-subunits in vivo, and the β_3-subunit, which has recently been shown to be essential for the in vivo anesthetic actions of etomidate and propofol. GABARs containing β_2- instead of β_3-subunits in α_4βδ- and α_6βδ-receptor combinations are almost 10 times less sensitive to EtOH, with threshold enhancement at 30 mM. GABARs containing γ_2- instead of δ-subunits with a_4β and α_6β are three times less sensitive to EtOH, with threshold responses at 100 mM, a concentration not usually reached with social EtOH consumption. These combined findings suggest that "extrasynap-tic" δ-subunit-containing GABARs, but not their "synaptic" γ-sub-unit-containing counterparts, are primary targets for EtOH.
机译：长期以来，γ-氨基丁酸A型受体（GABAR）参与介导乙醇（EtOH）的作用，但到目前为止，大多数已报道的重组GABAR组合仅在相当高的浓度（≥60 mM）时才显示EtOH反应。我们显示，含有δ-亚基的GABAR对γ-氨基丁酸高度敏感，缓慢失活，并被认为位于突触之外，在中等社会EtOH消费量的情况下，EtOH增强了其浓度。可再现的乙醇增强作用发生在3 mM处，其浓度比大多数州（0.08％wt / vol或17.4 mM）的法定血液酒精中毒（驾驶）限值低六倍。对这些低EtOH浓度有反应的GABAR需要GABARδ亚基（据认为仅与体内α_4-和α_6-亚基有关）和β_3-亚基（最近已证明对体内麻醉是必不可少的）依托咪酯和异丙酚的作用。在α_4βδ-和α_6βδ-受体组合中包含β_2-而不是β_3-亚基的GABAR对EtOH的敏感性几乎降低了10倍，阈值提高了30 mM。含有γ_2-而不是a_4β和α_6β的δ-亚基的GABAR对EtOH的敏感性低三倍，阈值响应为100 mM，这是社会EtOH消耗通常无法达到的浓度。这些综合的发现表明，“超突触”的含有δ-亚基的GABAR，而不是其“突触”的含有γ-亚基的对应物，是EtOH的主要靶标。

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