Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination
Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination
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巴比妥类药物与人类 GABAA 受体的相互作用：依赖于受体亚基组合
DOI：
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发表时间：
1996
影响因子：
7.3
通讯作者：
K. Wafford
中科院分区：
文献类型：
--
作者：
S. Thompson;Paul J. Whiting;K. Wafford
1在非洲爪蟾卵母细胞中表达含有不同α和β亚基以及γ2s亚基的人GABAA受体，并通过双电极电压钳方法电生理记录GABA电流来检查戊巴比妥对这些亚基组合的影响。2戊巴比妥先前已被证明对GABAA受体有三种作用：增强GABA反应，直接激活GABAA受体，以及在高浓度下阻断GABA氯离子通道。在本研究中，戊巴比妥活性由上述三种组分组成，对所有检测的亚基组合均有效。然而，亲和力和效力因受体亚型而异。3对于亲和力在20-35 μm范围内的所有亚基，戊巴比妥对GABA的增强作用发生在相同的浓度范围内。然而，所获得的增强程度从α1β2γ2s的GABA EC 20的236%变化到α6β2γ2s的536%。4戊巴比妥直接作用的检测表明，α亚基的类型决定了亲和力和疗效的程度。含有α6亚基的受体对戊巴比妥产生的最大直接反应大于最大GABA（最大GABA的150%至170%）。其他α亚基可获得的最大直接戊巴比妥反应范围为α5β2γ2s最大GABA的45%至α2β2γ2s的82%。戊巴比妥直接作用于α6β2γ2s的亲和力为58 μm，而其他α亚基的亲和力范围为α2β2γ2s的139 μm至α5β2γ2s的528 μm。5 β亚基的类型对戊巴比妥的直接作用的影响程度与α亚基的影响程度不同。对表达α6和γ2s的卵母细胞的亲和力或效力与β1、β2或β3之间无显著差异。对表达α1和γ2s的卵母细胞与β1、β2或β3的亲和力和效力显著不同，戊巴比妥对α1β3γ2s的亲和力和效力较高，其次是α1β2γ2s，然后是α1β1γ2s。6戊巴比妥的直接作用被印防己毒素阻断，但不被竞争性拮抗剂如荷包牡丹碱或SR95531阻断，表明戊巴比妥的直接激动剂活性不是通过GABA结合位点介导的。7首次证明了不同α和β亚基对戊巴比妥作用的影响。结果表明，含有α6亚基的GABAA受体对戊巴比妥的直接激活具有更高的亲和力和效力，并揭示戊巴比妥与GABAA受体上的多个位点结合，并且这些依赖于受体亚基组成。
1 Human GABAA receptors containing different α and β subunits with a γ2s subunit were expressed in Xenopus oocytes and the effects of pentobarbitone on these subunit combinations were examined by electrophysiological recording of GABA currents with the two‐electrode voltage‐clamp method. 2 Pentobarbitone has previously been shown to have three actions on GABAA receptors: a potentiation of GABA responses, a direct activation of GABAA receptors and, at high concentrations, a block of the GABA chloride channel. In this study pentobarbitone activity consisted of the above mentioned three components on all the subunit combinations tested. However, the affinities and efficacies varied with receptor subtype. 3 Potentiation of GABA by pentobarbitone occurred over the same concentration‐range for all the subunits with affinities in the range of 20–35 μm. The degree of potentiation obtained, however, varied from 236% of GABA EC20 on α1β2γ2s to 536% on α6β2γ2s. 4 Examination of the direct effect of pentobarbitone revealed that the type of α subunit present determines both the degree of affinity and efficacy obtained. Receptors containing an α6 subunit produced maximum direct responses to pentobarbitone larger than that obtainable with maximum GABA (150% to 170% of maximum GABA). The maximum direct pentobarbitone response obtainable with other α subunits ranged between 45% of maximum GABA for α5β2γ2s to 82% for α2β2γ2s. The affinity of the direct action of pentobarbitone on α6β2γ2s was 58 μm compared to affinities for the other α subunits ranging from 139 μm on α2β2γ2s to 528 μm on α5β2γ2s. 5 The type of β subunit present did not influence the direct action of pentobarbitone to the same extent as the α subunit. There were no significant differences between affinity or efficacy on oocytes expressing α6 and γ2s with β1, β2 or β3. Affinities and efficacies on oocytes expressing α1 and γ2s with β1, β2 or β3 were significantly different with pentobarbitone having a higher affinity and efficacy on α1β3γ2s followed by α1β2γ2s and then α1β1γ2s. 6 The direct effect of pentobarbitone was blocked by picrotoxin but not by competitive antagonists, such as bicuculline or SR95531, indicating that the direct agonist activity of pentobarbitone was not mediated via the GABA binding site. 7 For the first time the influence of the various α and β subunits on the effects of pentobarbitone were demonstrated. The results indicate that GABAA receptors containing α6 subunits have both a higher affinity and efficacy for direct activation by pentobarbitone, and reveal that pentobarbitone binds to more than one site on the GABAA receptor, and these are dependent on receptor subunit composition.
影响因子：
13.8
作者：
Geoffrey B. Smith;R. Olsen
通讯作者：
Geoffrey B. Smith;R. Olsen
同聚 β1 γ-氨基丁酸 A 型受体的新特性：麻醉剂丙泊酚和戊巴比妥的作用。
DOI：
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发表时间：
1995
期刊：
Molecular pharmacology.
影响因子：
--
作者：
Sanna,E;Garau,F;Harris,RA
通讯作者：
Harris,RA
γ-氨基丁酸A受体Cl-电流的增强与体内麻醉效力相关。
DOI：
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发表时间：
1994
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Zimmerman,SA;Jones,MV;Harrison,NL
通讯作者：
Harrison,NL