Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids
Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids
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镇静剂巴比妥类药物和孕烷类固醇对 GABAA 受体的调节
DOI：
10.1111/j.1476-5381.1988.tb11646.x
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发表时间：
1988
影响因子：
7.3
通讯作者：
A. Turner
中科院分区：
文献类型：
--
作者：
J. A. Peters;E. Kirkness;H. Callachan;J. Lambert;A. Turner
1 通过减少黄体酮和脱氧皮质酮代谢物对 γ-氨基丁酸 A (GABAA) 受体的调节，与抑制性巴比妥类药物产生的调节进行了比较：(a) 细胞培养物中牛酶法分离的嗜铬细胞的电压钳记录，以及 (b) [3H]-蝇蕈醇与猪脑膜制剂的特异性结合测定。 2 黄体酮代谢物 5α- 和 5β-pregnan-3α-ol-20-one (≥30 nm) 可逆且剂量依赖性地增强局部应用 GABA (100 μm) 引起的膜电流振幅，并且在 30 nM-100 μm 的浓度范围内刺激 [3H]-蝇蕈醇的结合。相比之下，5α-和5β-pregnan-3β-ol-20-one (30 nM-100 μm) 在这两种测定中几乎没有影响，表明类固醇作用具有显着的立体选择性。 3 配体结合数据的 Scatchard 分析表明，活性类固醇异构体的主要作用是可检测的 [3H]-蝇蕈醇结合位点的数量明显增加，而不是亲和力增加。 4 GABA 诱发电流也被雄酮 (1 μm) 和脱氧皮质酮代谢物 5α-pregnane-3α,21-diol-20-one (100 nm) 增强。 5 司可巴比妥 (10-100 μm)、戊巴比妥 (10-300 μm) 和苯巴比妥 (100-500 μm) 可逆且剂量依赖性地增强 GABA 诱发电流的振幅，而其反转电位没有任何变化。 6 在相对较高浓度 (≥ 30 μm) 下，司可巴比妥和戊巴比妥直接引发膜电流。结论是，此类电流是 GABAA 受体通道激活的结果，因为它们与 GABA 诱发的反应 (≥0mV) 具有共同的逆转电位，被荷包牡丹碱 (3 μm) 可逆地拮抗，并被地西泮 (1 μm) 或 5β-pregnan-3α-ol-20-one (500 nm) 增强。 7 司可巴比妥 (1 μm-1 mm) 剂量依赖性增强 [3H]-蝇蕈醇的结合。与活性类固醇一样，表观结合位点数量的增加是造成这种效应的原因。 8 配体结合测定中司可巴比妥的饱和浓度 (1 mm) 不会抑制 5β-pregnan-3α-ol-20-one (30 nM-100 μm) 产生的对照结合的增强程度。同样，浓度为 100 μm 的类固醇不影响司可巴比妥 (1 μm-1 mm) 对 [3H]-蕈醇结合的增强作用。在所有测试的浓度组合中，司可巴比妥和 5β-pregnan-3α-ol-20-one 对 [3H]-蝇蕈醇结合的影响是相加的。 9 结合之前发表的观察结果，目前的数据表明巴比妥类药物和类固醇的 GABA 模拟和增强作用非常相似。然而，在配体结合测定中使用类固醇和巴比妥类药物的组合获得的结果似乎与两类化合物与共同位点相互作用以调节 GABAA 受体活性不一致。
1 The modulation of the γ‐aminobutyric acidA (GABAA) receptor by reduced metabolites of progesterone and deoxycorticosterone has been compared with that produced by depressant barbiturates in: (a) voltage‐clamp recordings from bovine enzymatically isolated chromaffin cells in cell culture, and (b) an assay of the specific binding of [3H]‐muscimol to a preparation of porcine brain membranes. 2 The progesterone metabolites 5α‐ and 5β‐pregnan‐3α‐ol‐20‐one (≥30 nm) reversibly and dosedependently enhanced the amplitude of membrane currents elicited by locally applied GABA (100 μm), and over the concentration range 30 nM‐100 μm stimulated the binding of [3H]‐muscimol. In contrast, 5α‐ and 5β‐pregnan‐3β‐ol‐20‐one (30 nM‐100 μm) had little effect in either assay, indicating a marked stereoselectivity of steroid action. 3 Scatchard analysis of the ligand binding data suggested an apparent increase in the number, rather than the affinity, of detectable [3H]‐muscimol binding sites as the principle action of the active steroid isomers. 4 GABA‐evoked currents were also potentiated by androsterone (1 μm) and the deoxycorticosterone metabolite 5α‐pregnane‐3α,21‐diol‐20‐one (100 nm). 5 Secobarbitone (10–100 μm), pentobarbitone (10–300 μm) and phenobarbitone (100–500 μm) reversibly and dose‐dependently potentiated the amplitude of GABA‐evoked currents in the absence of any change in their reversal potential. 6 At relatively high concentrations (≥ 30 μm) secobarbitone and pentobarbitone directly elicited a membrane current. It is concluded that such currents result from GABAA receptor‐channel activation since they share a common reversal potential with GABA‐evoked responses (≥0mV), are reversibly antagonized by bicuculline (3 μm), and potentiated by either diazepam (1 μm) or 5β‐pregnan‐3α‐ol‐20‐one (500 nm). 7 Secobarbitone (1 μm‐1 mm) dose‐dependently enhanced the binding of [3H]‐muscimol. In common with the active steroids, an increase in the apparent number of binding sites was responsible for this effect. 8 A saturating concentration (1 mm) of secobarbitone in the ligand binding assay did not suppress the degree of enhancement of control binding produced by 5β‐pregnan‐3α‐ol‐20‐one (30 nM‐100 μm). Similarly the steroid, at a concentration of 100 μm, did not influence the enhancement of [3H]‐muscimol binding by secobarbitone (1 μm‐1 mm). In all combinations of concentrations tested, the effects of secobarbitone and 5β‐pregnan‐3α‐ol‐20‐one on [3H]‐muscimol binding were additive. 9 In conjunction with previously published observations, the present data indicate close similarities in the GABA‐mimetic and potentiating actions of barbiturates and steroids. However, the results obtained with combinations of steroids and barbiturates in the ligand binding assay appear inconsistent with the two classes of compound interacting with a common site to modulate the GABAA receptor activity.
1-甲基-5-苯基-5-丙基巴比妥酸光学异构体的不同作用位点在 GABA 受体复合物上具有相反的药理活性。
影响因子：
5
作者：
Ticku,MK;Rastogi,SK;Thyagarajan,R
通讯作者：
Thyagarajan,R
影响因子：
3.6
作者：
R. Squires;J. Casida;M. Richardson;E. Saederup
通讯作者：
R. Squires;J. Casida;M. Richardson;E. Saederup
GABA/苯二氮卓受体复合物上的巴比妥类识别位点与印防己毒素/TBPS 识别位点不同。
影响因子：
5
作者：
Trifiletti,RR;Snowman,AM;Snyder,SH
通讯作者：
Snyder,SH