REGULATION AND TURNOVER OF THE BENZODIAZEPINE RECEPTOR

这项研究的目的是了解一种分子 调控机制和/或化学信号的水平 神经细胞中受体的数量、亲和力和分布。在……里面 具体地说，我们希望确定受体的控制机制 神经元的数量和分布与非神经细胞的数量和分布相比。 虽然对受体的周转(合成和降解)知道得很多 据我们所知，非神经细胞没有 一种定位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都已经 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 如果监管机构的命运 受体后面直接跟随一个特定的探针，该探针不会改变 受体周转率。 我们已经证明，培养中的神经元对药物的敏感性 次要的苯二氮卓类药物可增强γ-氨基丁酸的作用 镇静剂、抗惊厥药和骨骼肌松弛药可能 通过增强中枢神经系统中的抑制性神经元活性来发挥作用。结果是 结合结合和电生理实验符合 功能性高亲和力苯二氮卓类受体的存在 用氟硝西潘作为一种特殊的和不可逆转的标签 光亲和配体。初步实验表明，苯二氮类药物 用这个探针可以研究受体的周转。这些研究将 根据目前的提案，可以延长。 这项提案的主要目标是：1)调查 生物合成和降解步骤与维护的关系 和2)决定急性和长期的影响。 受体与配体的接触对受体数量和/或亲和力的影响 细胞培养来源于胚胎鸡脑和脊髓。

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.