MECHANISMS OF BLOCK OF NMDA-ACTIVATED CHANNELS

描述（改编自申请人的摘要）： 建议的研究是为了加深我们对结构，功能， 和抑制负责突触的受体分子 传输 这项研究将集中在谷氨酸受体的一种亚型上 由N-甲基-D-天冬氨酸（NMDA）特异性激活。 的家人 由神经递质谷氨酸激活的兴奋性受体， 负责大部分的快速突触内的通信 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。 也直接或间接地 涉及许多神经系统疾病，包括癫痫，精神分裂症， 局部缺血和多种退行性疾病。 更好地了解 一个受体参与的是这样一个显着的范围内的过程，在正常和 患病的神经系统将导致预防能力增强，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 Mg 2+对NMDA形成的离子传导通道的调节阻断 受体的 Mg 2+，来自细胞外（Mg 2 +e）和细胞内 (Mg2+i）膜的两侧，可以进入NMDA激活的通道，和 阻碍离子的流动。 Mg 2 + 1的阻断将使用 膜片钳技术来测量跨膜电流， 培养的神经元和中国仓鼠卵巢（CHO）细胞， 经遗传修饰以表达NMDA受体。 的机制 Mg 2 + 1抑制神经元和CHO细胞反应将通过以下方法研究： 同时测定NMDA反应和Mg ~（2+）浓度。 许多药物可以阻断NMDA激活的通道。 对人类的影响 这些药物的种类繁多：有些起致幻剂的作用， 其他药物在临床上耐受良好，并用于治疗 神经退行性疾病 这类药物抑制 NMDA受体将在拟议的研究中进行检查。 的影响 阻断剂和通道之间相互作用的永久离子也将被 研究了 最后，将结果整合到动力学模型中 通道阻滞剂与NMDA受体的相互作用。 通过建模 并通过几种不同化合物的阻聚比较， 阻断剂-通道相互作用及其对阻断剂结构的依赖性将 发展。 研究结果将有助于我们更好地理解渠道 功能以及它如何受到药物结合的影响，并可能促进 临床上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.