Lambert J J, Peters J A, Sturgess N C, Hales T G
Department of Pharmacology & Clinical Pharmacology, Ninewells Hospital & Medical School, Dundee University, UK.
Ciba Found Symp. 1990;153:56-71; discussion 71-82. doi: 10.1002/9780470513989.ch4.
The effect of some endogenous and synthetic steroids on the operation of inhibitory and excitatory amino acid neurotransmitter receptors was examined. Anaesthetic pregnane steroids (e.g. alphaxalone, 5 alpha-pregnan-3 alpha-ol-20-one, 5 alpha-pregnane-3 alpha,21-diol-20-one) potentiated GABAA receptor-mediated whole-cell currents recorded from bovine chromaffin cells. The threshold concentration for enhancement was 10-30 nM. Potentiation was stereoselective and was mediated by a steroid-induced prolongation of the burst duration of the GABA-activated channel. Additionally, the pregnane steroids directly activated the GABAA receptor. Both the potentiation and activation appear to be mediated through a site(s) distinct from the well-known barbiturate and benzodiazepine allosteric sites of the GABAA receptor. Intracellularly applied alphaxalone and 5 beta-pregnan-3 alpha-ol-20-one had no discernible effects on the GABAA receptor, suggesting that the steroid binding site can only be accessed extracellularly. Unlike behaviourally depressant barbiturates, which modulate GABAA receptor function in a manner similar to that of the pregnane steroids, alphaxalone and 5 beta-pregnan-3 alpha-ol-20-one show striking pharmacological selectivity. Voltage-clamp recordings from rat central neurons in culture indicate that pentobarbitone exerts its potentiating and GABA-mimetic effects over a range of concentrations which also depress currents mediated by glutamate receptor subtypes. In contrast, alphaxalone and several endogenous steroids greatly enhance responses to GABA, but have no direct effect on glutamate receptors. Such pharmacological selectivity, coupled with appropriate stereoselectivity of action, suggests that the GABAA receptor mediates some of the behavioural effects of synthetic and endogenous pregnane steroids.
研究了一些内源性和合成类固醇对抑制性和兴奋性氨基酸神经递质受体作用的影响。麻醉性孕烷类固醇（如阿法沙龙、5α-孕烷-3α-醇-20-酮、5α-孕烷-3α,21-二醇-20-酮）增强了从牛嗜铬细胞记录到的GABAA受体介导的全细胞电流。增强作用的阈值浓度为10 - 30 nM。增强作用具有立体选择性，是由类固醇诱导的GABA激活通道爆发持续时间延长介导的。此外，孕烷类固醇直接激活GABAA受体。增强作用和激活作用似乎都是通过与GABAA受体著名的巴比妥类和苯二氮䓬类变构位点不同的位点介导的。细胞内应用阿法沙龙和5β-孕烷-3α-醇-20-酮对GABAA受体没有明显影响，这表明类固醇结合位点只能从细胞外进入。与行为抑制性巴比妥类药物不同，后者以与孕烷类固醇相似的方式调节GABAA受体功能，阿法沙龙和5β-孕烷-3α-醇-20-酮表现出显著的药理选择性。来自培养的大鼠中枢神经元的电压钳记录表明，戊巴比妥在一系列浓度下发挥其增强作用和GABA模拟作用，这些浓度也会抑制由谷氨酸受体亚型介导的电流。相比之下，阿法沙龙和几种内源性类固醇大大增强了对GABA的反应，但对谷氨酸受体没有直接影响。这种药理选择性，再加上适当的作用立体选择性，表明GABAA受体介导了合成和内源性孕烷类固醇的一些行为效应。
