REGULATION AND TURNOVER OF THE BENZODIAZEPINE RECEPTOR

我们研究的长期目标是在分子水平上 水平，动态调节神经递质的控制机制 受体分布和功能。 γ-氨基丁酸-A受体（GABA-A-R）特别是 在这方面的兴趣，既因为它是一个最广泛的 在神经系统中分布着神经递质受体， 它是三个重要药物家族的靶点-苯并二氮杂卓类， 巴比妥酸盐和类固醇-它们与不同的调节性蛋白结合， 在GABA-A-R上。 值得注意的是，这些调节剂的相互作用 与GABA-A-R本身是受调节，以应对慢性 暴露于这些和其他药物，包括发射器，GABA。 本研究的目的是探讨GABA-A-R的作用机制。 在原代单层细胞培养系统中的调节。 为此， 放射性配体结合、分子生物学、36-Cl摄取和 电生理学将被用来调查的原因，机制， 和GABA-A-R调节的后果。 特别是，我们将定义 类固醇调节GABA-A-R的药理学，并将涉及 GABA-A-R亚单位基因表达的变化， 受体的配体结合特性。

The long-term goal of our research is to understand, on a molecular level, the control mechanisms that dynamically regulate neurotransmitter receptor distribution and function. The gamma-aminobutyric acid-A receptor (GABA-A-R) is of particular interest in this respect, both because it is one of the most widely distributed neurotransmitter receptors in the nervous system, and because it is a target for three important families of drugs-the benzodiazepines, the barbiturates, and the steroids-which bind to distinct modulatory sites on the GABA-A-R. Remarkably, the interaction of these modulators with the GABA-A-R is itself subject to regulation in response to chronic exposure to these and other drugs, including the transmitter, GABA. The goals of this proposal are to investigate mechanisms of GABA-A-R regulation in a primary monolayer cell culture system. Toward this end, the methods of radioligand binding, molecular biology, 36-Cl uptake, and electrophysiology will be employed to investigate the causes, mechanisms, and consequences of GABA-A-R regulation. In particular, we will define the pharmacology of GABA-A-R regulation by steroids, and will relate changes in GABA-A-R subunit gene expression to functional and ligand-binding properties of the receptor.