MECHANISMS OF BLOCK OF NMDA-ACTIVATED CHANNELS

描述(改编自申请人的摘要)： 提出的研究是为了加深我们对其结构、功能、 和抑制负责突触的受体分子 变速箱。这项研究将集中在谷氨酸受体的一个亚型上 被N-甲基-D-天冬氨酸(NMDA)特异性激活。他的家人 由神经递质谷氨酸激活的兴奋性受体是 负责大多数快速突触通信在 脊椎动物的神经系统。NMDA受体被认为是 在突触传递、突触可塑性和 神经系统的发育。它还直接或间接地 与许多神经系统疾病有关，包括癫痫、精神分裂症、 缺血，以及各种退行性疾病。更好地理解 参与其中的受体是如此广泛的正常和 患病的神经系统将导致预防或 改善神经系统功能障碍的后果。 可能是因为它必须在许多神经系统中发挥作用，NMDA 受体受多种机制调控。NMDA受体的一种模式 镁离子对NMDA形成的离子传导通道的调节阻断作用 受体。胞外和胞内的镁离子 膜的(Mg2+i)侧，可以进入NMDA激活的通道，并 阻挡离子的流动。由镁离子I形成的块将使用 膜片钳技术测量细胞膜上的电流 培养的神经元和中国仓鼠卵巢(CHO)细胞 通过基因改造来表达NMDA受体。这一机制通过它 镁离子抑制神经元和CHO细胞的反应将通过 同时测定NMDA反应和镁离子浓度。 许多药物可以阻断NMDA激活的通道。对人类的影响 这些药物是多种多样的：有些是迷幻剂，也可以用作毒品 滥用；其他的在临床上耐受性很好，并用于治疗 神经退行性疾病。这类药物抑制的机制 NMDA受体将在拟议的研究中进行检查。的影响 永久离子对阻滞剂和通道之间的相互作用也会产生影响 调查过了。最后，结果将被集成到动力学模型中 通道阻滞剂与NMDA受体的相互作用。通过建模 并用几种不同的化合物比较块，基本规则是 阻滞剂-通道相互作用及其对阻滞剂结构的依赖将 被开发出来。研究结果将提高我们对渠道的认识 功能，以及药物结合如何影响它，并可能促进 临床有用的神经保护剂的设计。

DESCRIPTION (Adapted from applicant's abstract): The broad objective of the proposed research is to deepen our understanding of the structure, function, and inhibition of the receptor molecules responsible for synaptic transmission. The research will focus on a subtype of glutamate receptor specifically activated by N-methyl-D-aspartate (NMDA). The family of excitatory receptors activated by the neurotransmitter glutamate is responsible for the majority of fast synaptic communications within the vertebrate nervous system. The NMDA receptor is thought to be of fundamental importance in synaptic transmission, synaptic plasticity, and development of the nervous system. It is also directly or indirectly involved in many nervous system diseases, including epilepsy, schizophrenia, ischemia, and a variety of degenerative diseases. Improved understanding of a receptor involved is such a remarkable range of processes in normal and diseased nervous systems will lead to an enhanced ability to prevent, or ameliorate the consequences of, nervous system dysfunction. Possibly because it must function in numerous neural systems, the NMDA receptor is regulated by multiple mechanisms. One mode of NMDA receptor regulation blockade by Mg2+ of the ion-conducting channel formed by the NMDA receptor. Mg2+, both from the extracellular (Mg2+e) and intracellular (Mg2+i) sides of the membrane, can enter the NMDA-activated channel and obstruct the flow of ions. Block by Mg2+i will be studied using the patch-clamp technique to measure current flow across the membranes of cultured neurons and of Chinese hamster ovary (CHO) cells that have been genetically modified to express NMDA receptors. The mechanism by which Mg2+i inhibits neuronal and CHO cell responses will be investigated by simultaneously measuring NMDA responses and the concentration of Mg2+i. Numerous drugs can block the NMDA-activated channel. The effects on humans of these drugs are diverse: some act as hallucinogens and are used as drugs of abuse; others are well tolerated clinically and are used in the treatment of neurodegenerative diseases. The mechanisms by which such drugs inhibit NMDA receptors will be examined in the proposed research. The influence of permanent ions on the interaction between blocker and channel also will be investigated. Finally, the results will be integrated into a kinetic model of the interaction of channel blockers with the NMDA receptor. By modeling and comparing block by several different compounds, basic rules of blocker-channel interactions and their dependence on blocker structure will be developed. The results will improve our understanding of channel function and how it can be influenced by drug binding, and may facilitate the design of clinically useful neuroprotective agents.