Assessment of direct gating and allosteric modulatory effects of meprobamate in recombinant GABA(A) receptors.
Assessment of direct gating and allosteric modulatory effects of meprobamate in recombinant GABA(A) receptors.
复制标题
评估甲丙氨酯在重组 GABA(A) 受体中的直接门控和变构调节作用。
DOI：
10.1016/j.ejphar.2016.02.031
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发表时间：
2016
影响因子：
5
通讯作者：
Dillon,GlennH
中科院分区：
文献类型：
--
作者：
Kumar,Manish;Dillon,GlennH
甲丙氨酯是一种IV级抗焦虑药，是肌肉松弛剂卡立普多的主要代谢产物。甲丙氨酯调节GABAA（γ-氨基丁酸A型）受体，并具有巴比妥类活性。为了深入了解其作用，我们使用重组GABA A受体进行了一系列研究。在αxβzγ2 GABAA受体（其中x=1−6和z=1−3）中，所有α亚基亚型都明显具有增强GABA介导电流的能力，在α5表达受体中观察到的效应最大。所有α亚基均存在直接门控，尽管在α3表达受体中减弱。在α1β1γ2和α1β2γ2受体中，变构和直接效应相当，而与α1β2γ2受体相比，α1β2受体中的变构效应增强。在突触外受体（α1β3δ和α4β3δ），甲丙氨酯增强EC 20和饱和GABA电流，直接激活这些受体。巴比妥类拮抗剂美解眠可减弱甲丙氨酯的直接作用。戊巴比妥直接门控同聚体β3受体，而甲丙氨酯则不能，而是阻断这些受体中存在的自发开放电流。在野生型同型ρ1受体中，戊巴比妥和甲丙氨酯在直接门控中无效;已知赋予戊巴比妥敏感性的突变不赋予甲丙氨酯敏感性。我们的研究结果提供了对甲丙氨酯和母体治疗药物（如卡立普多）作用的深入了解。而在一般行动的甲丙氨酯的卡立普多，不同的影响，甲丙氨酯在某些受体亚型表明，潜在的优势，甲丙氨酯可以利用。重新评估以前合成的甲丙氨酯相关的氨基甲酸酯分子的肌肉松弛剂和其他治疗适应症是必要的。
Meprobamate is a schedule IV anxiolytic and the primary metabolite of the muscle relaxant carisoprodol. Meprobamate modulates GABAA(γ-aminobutyric acid Type A) receptors, and has barbiturate-like activity. To gain insight into its actions, we have conducted a series of studies using recombinant GABAAreceptors. In αxβzγ2 GABAAreceptors (where x=1−6 and z=1−3), the ability to enhance GABA-mediated current was evident for all α subunit isoforms, with the largest effect observed in α5-expressing receptors. Direct gating was present with all α subunits, although attenuated in α3-expressing receptors. Allosteric and direct effects were comparable in α1β1γ2 and α1β2γ2 receptors, whereas allosteric effects were enhanced in α1β2 compared to α1β2γ2 receptors. In “extrasynaptic” (α1β3δ and α4β3δ) receptors, meprobamate enhanced EC20and saturating GABA currents, and directly activated these receptors. The barbiturate antagonist bemegride attenuated direct effects of meprobamate. Whereas pentobarbital directly gated homomeric β3 receptors, meprobamate did not, and instead blocked the spontaneously open current present in these receptors. In wild type homomeric ρ1 receptors, pentobarbital and meprobamate were ineffective in direct gating; a mutation known to confer sensitivity to pentobarbital did not confer sensitivity to meprobamate. Our results provide insight into the actions of meprobamate and parent therapeutic agents such as carisoprodol. Whereas in general actions of meprobamate were comparable to those of carisoprodol, differential effects of meprobamate at some receptor subtypes suggest potential advantages of meprobamate may be exploited. A re-assessment of previously synthesized meprobamate-related carbamate molecules for myorelaxant and other therapeutic indications is warranted.