Molecular actions of pentobarbital isomers on sodium channels from human brain cortex.
Molecular actions of pentobarbital isomers on sodium channels from human brain cortex.
复制标题
戊巴比妥异构体对人脑皮质钠通道的分子作用。
DOI：
10.1097/00000542-199004000-00012
复制
发表时间：
1990
期刊：
影响因子：
8.8
通讯作者：
Urban,BW
中科院分区：
文献类型：
--
作者：
Frenkel,C;Duch,DS;Urban,BW
新的平面脂质双层技术使人脑单一钠通道的药理学研究成为可能，克服了传统实验制剂中组织可利用性和蛋白质功能迅速丧失的局限性。从人脑皮质组织制备突触体囊泡，将其与平面脂质双层融合。在巴曲霉毒素存在的情况下，将钠离子通道掺入脂双层，并研究其单通道特性。研究发现，戊巴比妥抑制钠通道的两个主要功能，导致电压无关的通道开放时间(ED50为0.61-0.75 mm)缩短，并与电压依赖的稳态激活相互作用。稳态激活曲线向更负的电位移动，斜率减小，即负的膜电位在关闭钠通道时的作用减弱。这一结果与戊巴比妥诱导的蛋白质灵活性增加是一致的。戊巴比妥类的两种光学立体异构体的作用无显著差异，提示巴比妥类药物的临床作用可能还涉及其他离子通道。戊巴比妥对钠通道的影响发生在被认为与全身麻醉相关的浓度和临床范围内。这表明钠通道可能有助于全身麻醉抑制，支持我们的假设，即麻醉是几种麻醉作用在分子水平上叠加和整合的结果。
New planar lipid bilayer technology enabled the pharmacologic study of single sodium channels from human brain, overcoming the limitations of tissue availability and the rapid loss of protein function in conventional experimental preparations. Synaptosomal vesicles prepared from human brain cortical tissue were fused with planar lipid bilayers. In the presence of batrachotoxin, sodium channels were incorporated into lipid bilayers and their single-channel properties studied. Pentobarbital was found to depress two major functions of the sodium channel, leading to a voltage-independent reduction of the fractional channel open-time (ED50 0.61-0.75 mM) and an interaction with the voltage-dependent steady-state activation. The steady-state activation curve was shifted to more negative potentials and had a reduced slope, ie, negative membrane potentials became less effective at closing sodium channels. The results were consistent with a pentobarbital-induced increase in protein flexibility. The actions of the two optical stereoisomers of pentobarbital showed no significant differences, indicating that other ion channels must also be involved in the clinical actions of barbiturates. The pentobarbital effects on sodium channels occurred at concentrations thought to be relevant in general anesthesia and within the clinical range. This suggests that sodium channels could contribute to overall anesthetic depression, supporting our hypothesis that anesthesia results from the superposition and integration of several anesthetic actions at the molecular level.