REGULATION AND TURNOVER OF THE BENZODIAZEPINE RECEPTOR

这项研究的目的是了解，在分子上， 水平，控制机制和/或化学信号，调节 受体数量、亲和力和分布。 在 特别是，我们希望确定如何控制受体的机制， 神经元中的数量和分布与非神经细胞中的数量和分布相比。 虽然对受体周转（合成和降解）有很多了解，但在 非神经细胞，据我们所知，没有 对局部受体的合成和降解的深入研究 到中枢神经系统。 许多已经出现的作品 关注受体数量的“下调”或“上调”; 然而，这种变化的动力学只能提供有限的信息 关于受体合成和降解的细胞机制。 受体 监管可能会更有意义的调查，如果命运的 受体后直接与一个特定的探针，不改变 受体周转率。 我们已经表明，培养的神经元对化疗药物的敏感性， γ-氨基丁酸被苯二氮卓类药物增强， 镇静剂、抗惊厥药和骨骼肌松弛剂， 通过增强CNS中的抑制性神经元活性起作用。 的结果 结合和电生理学实验的结合与 存在功能性高亲和力苯二氮受体， 用氟硝西泮特异性和不可逆地标记， 光亲和配体 初步实验表明苯二氮卓类药物 可以用该探针研究受体转换。 这些研究将 根据目前的建议，将延长。 本提案的主要目标是：（1）调查 生物合成和降解步骤与维护的关系 2）确定急性和长期的影响 受体暴露于配体对受体数量和/或亲和力的影响，使用 来自鸡胚脑和脊髓的细胞培养物。

The goal of this research is to gain an understanding, on a molecular level, of the control mechanisms and/or chemical signals that regulate receptor number, affinity and distribution in neuronal cells. In particular, we wish to determine how mechanisms for control of receptor number and distribution in neurons compare to those in non-neural cells. While much is known of receptor turnover (synthesis and degradation) in non-neural cells, there have been, to the best of our knowledge, no thorough studies of the synthesis and degradation of a receptor localized to the central nervous system. Much of the work that has appeared has focused upon 'down-regulation' or 'up-regulation' of receptor numbers; however, the kinetics of such changes provide only limited information about cellular mechanisms of receptor synthesis and degradation. Receptor regulation may be investigated more meaningfully if the fate of the receptor is followed directly with a specific probe that does not alter the rates of receptor turnover. We have shown that the chemosensitivity of neurons in culture to gamma-aminobutyric acid is potentiated by benzodiazepines which are minor tranquilizers, anticonvulsants and skeletal muscle relaxants that probably act by enhancing inhibitory neuronal activity in the CNS. The results of combined binding and electrophysiological experiments are consistent with the presence of a functional high affinity benzodiazepine receptor that can be specifically and irreversibly labeled with flunitrazepam as a photoaffinity ligand. Initial experiments suggest that benzodiazepine receptor turnover can be investigated with this probe. These studies will be extended under the current proposal. The principal objectives of this proposal are 1) to investigate the relationship of the biosynthetic and degradative steps to the maintenance of receptor number, and 2) o determine the effects of acute and long term exposure of receptor to ligands on receptor number and/or affinity, using cell cultures derived from embryonic chick brain and spinal cord.