REGULATION AND TURNOVER OF THE BENZODIAZEPINE RECEPTOR

中枢神经系统中化学突触处的突触传递涉及一种 描述得比较详细的事件序列， 神经递质从突触前末梢释放， 与抑制配体结合的突触后受体相互作用 转化为突触后反应 神经生物学中的一个主要问题 是突触后受体如何被调节以适应不断变化的环境。 GABAA/苯并二氮杂卓受体（GABA/BZD-R）特别是 在这方面的兴趣，因为响应其发射机， GABA通过苯二氮卓类（BZD）变构调节， 作用于GABA/BAD-R上的单独位点。 值得注意的是， BZD与GABA/BZD-R的调节相互作用本身是受 对慢性BZD暴露的调节，而且， 调节方式与慢性炎症引起的调节方式不同， 暴露于GABA能激动剂。 而长期暴露于 GABA能激动剂导致GABA/BZD-R水平下调， 长期接触BZD会导致 BZD识别位点和BZD识别位点之间的变构相互作用 GABA识别位点，受体水平无变化。 因此，在本发明中， GABA/BZD-R表现出两种独立的同源模式， 调节：GABA能激动剂诱导的下调，和 BZD诱导的解偶联。 此外，现已发现GABA/BZD-R表现出异源性， 调节对慢性暴露于甲基黄嘌呤，如 如咖啡因和茶碱，它们也产生GABA的解偶联， 和BZD识别位点，但它们可能通过一个 腺苷受体 该提案的目的是研究同源 原代单层细胞中GABA/BZD-R的异源调节 文化 为此，放射性配体结合的方法，36 C1 摄取和电生理学将被用来确定 同源和异源的原因、机制和后果 GABA/BZD-R调节。

Synaptic transmission at chemical synapses in the CNS involves a relatively well-described sequences of events in which neurotransmitter is released from the presynaptic terminal and interacts with postsynaptic receptors that transduce ligand binding into a postsynaptic response. A major questions in neurobiology is how postsynaptic receptors are regulated to changing conditions. The GABAA/benzodiazepine receptor (GABA/BZD-R) is of particular interest in this respect, since the response to its transmitter, GABA, is allosterically modulated by benzodiazepines (BZDs) which act at a separate site on the GABA/BAD-R. Remarkably, the modulatory interaction of BZDs with th GABA/BZD-R is itself subject to regulation in response to chronic BZD exposure, and, moreover, the mode of regulation differs form that elicited by chronic exposure to GABAergic agonists. Whereas chronic exposure to GABAergic agonists results in down-regulation of GABA/BZD-R levels, chronic exposure to BZDs results in an "uncoupling" of the allosteric interaction between the BZD recognition site and the GABA recognition site, with no change in receptor levels. Thus, the GABA/BZD-R exhibits two independent modes of homologous regulations: down-regulation induced by GABAergic agonists, and uncoupling induced by BZDs. Moveover, the GABA/BZD-R has now been found to exhibit heterologous regulation in response to chronic exposure to methylxanthines, such as caffeine and theophylline, which also produce uncoupling of GABA and BZD recognition sites, but which probably act through an adenosine receptor. The goal of this proposal is to investigate mechanism of homologous and heterologous GABA/BZD-R regulation in primary monolayer cell culture. Toward this end, the methods of radioligand binding, 36C1 uptake, and electrophysiology will be employed to determine the causes, mechanisms, and consequences of homologous and heterologous GABA/BZD-R regulation.