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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Low-dose alcohol actions on α4β3δ GABA_A receptors are reversed by the behavioral alcohol antagonist Ro15-4513
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Low-dose alcohol actions on α4β3δ GABA_A receptors are reversed by the behavioral alcohol antagonist Ro15-4513

机译：行为性酒精拮抗剂Ro15-4513逆转了对α4β3δGABA_A受体的低剂量酒精作用

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摘要

Although it is now more than two decades since it was first reported that the imidazobenzodiazepine Ro15-4513 reverses behavioral alcohol effects, the molecular target(s) of Ro15-4513 and the mechanism of alcohol antagonism remain elusive. Here, we show that Ro15-4513 blocks the alcohol enhancement on recom-binant "extrasynaptic" α4/6β3δ GABA_A receptors at doses that do not reduce the GABA-induced Cl~- current. At low ethanol concentrations ( ≤ 30 mM), the Ro15-4513 antagonism is complete. However, at higher ethanol concentrations ( ≥ 100 mM), there is a Ro15-4513-insensitive ethanol enhancement that is abolished in receptors containing a point mutation in the second transmem-brane region of the β3 subunit (β3N265M). Therefore, α4/6β3δ GABA receptors have two distinct alcohol modulation sites: (ⅰ) a low-dose ethanol site present in α4/6β3δ receptors that is antagonized by the behavioral alcohol antagonist Ro15-4513 and (ⅱ) a site activated at high (anesthetic) alcohol doses, defined by mutations in membrane-spanning regions. Receptors composed of α4β3N265Mδ subunits that lack the high-dose alcohol site show a saturable ethanol dose-response curve with a half-maximal enhancement at 16 mM, close to the legal blood alcohol driving limit in most U.S. states (17.4 mM). Like in behavioral experiments, the alcohol antagonist effect of Ro15-4513 on recombinant α4β3δ receptors is blocked by flumazenil and β-carboline-ethyl ester (β-CCE). Our findings suggest that ethanol/Ro15-4513-sensitive GABA_A receptors are important mediators of behavioral alcohol effects.
机译：尽管自从首次报道咪唑基苯并二氮杂Ro15-4513逆转行为酒精效应以来已经过去了二十多年，但Ro15-4513的分子靶标和酒精拮抗机制仍然难以捉摸。在这里，我们显示Ro15-4513在不降低GABA诱导的Cl〜-电流的剂量下阻断重组“突触外”α4/6β3δGABA_A受体的醇增强作用。在低乙醇浓度（≤30 mM）下，Ro15-4513拮抗作用完成。但是，在更高的乙醇浓度（≥100 mM）下，对Ro15-4513不敏感的乙醇增强作用会消失，该增强作用在β3亚基第二个跨膜区（β3N265M）中含有点突变的受体中消失。因此，α4/6β3δGABA受体具有两个不同的醇调节位点：( :)存在于α4/6β3δ受体中的低剂量乙醇位点，被行为性酒精拮抗剂Ro15-4513拮抗，并且（ⅱ）在高浓度时被激活（麻醉剂）的酒精剂量，由跨膜区域的突变定义。由缺乏高剂量酒精位点的α4β3N265Mδ亚基组成的受体显示出可饱和的乙醇剂量-响应曲线，在16 mM处有一半的最大增强，接近美国大多数州的法定血液酒精驱动极限（17.4 mM）。像在行为实验中一样，Ro15-4513对重组α4β3δ受体的醇拮抗作用被氟马西尼和β-咔啉乙酯（β-CCE）阻断。我们的发现表明，乙醇/ Ro15-4513敏感的GABA_A受体是行为酒精效应的重要介体。

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