REGULATION AND TURNOVER OF THE BENZODIAZEPINE RECEPTOR

中枢神经系统化学突触的突触传递涉及 相对描述较好的事件序列，其中 神经递质从突触前终末释放出来 与转导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 突触后受体是如何根据不断变化的条件进行调节的。 GABAA/苯二氮卓受体(GABA/BZD-R)是一种特殊的受体 对这方面的兴趣，因为对其发射机的回应， GABA，是由苯二氮卓类(BZD)变构调制的 在GABA/BAD-R上的单独位置执行操作。值得注意的是， BZDS与TH-GABA/BZD-R的调制相互作用本身就是研究对象 应对长期接触BZD的监管，此外， 这一调控模式与慢性病引发的调控模式不同 暴露于GABA能激动剂。鉴于长期接触 GABA能激动剂导致GABA/BZD-R水平下调， 长期暴露于BZD会导致 BZD识别位点与BZD的变构相互作用 GABA识别位点，受体水平不变。因此， GABA/BZD-R呈现两种独立的同源模式 调节：GABA能激动剂诱导的下调，以及 BZDS诱导的解偶联作用。 此外，现已发现GABA/BZD-R表现出异源 对长期接触甲基黄嘌呤的监管，如 咖啡因和茶碱，这也会产生GABA的解偶联 和BZD识别站点，但它们可能通过 腺苷受体。 这一建议的目的是为了研究同源基因的作用机制。 和异源GABA/BZD-R对原代单层细胞的调节 文化。为此，放射性配基结合的方法，36c1 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.