Interaction of Permeant and Blocking Ions with NMDA Receptors

描述（由申请人提供）：项目摘要。由神经递质L-谷氨酸激活的兴奋性受体介导脊椎动物神经系统中的大多数兴奋性突触传递。在拟定研究中，将研究N-甲基-D-天冬氨酸（NMDA受体）激活的谷氨酸受体亚型。NMDA受体对于许多基本神经系统功能（包括学习和发育）是必需的，并且涉及一系列显著的神经系统疾病，包括许多精神障碍。拟议研究的长期目标是了解NMDA受体的功能和结构特性，这些受体在脑功能中起着多种作用。 可能是因为它们参与多个神经系统，NMDA受体受到许多形式的生理调节。最有力的调节形式之一是通过细胞外镁离子（Mg 2 + 0）阻断NMDA受体的离子通道。Mg 2 + 0对通道的阻滞作用是NMDA受体参与脑功能的基本决定因素。几种重要的药物也能阻断NMDA受体的通道。Mg 2 + 0和通道阻断药物与NMDA受体的相互作用反过来也受到高度调节。在所提出的研究中，我们将调查的几个机制，其中通道阻滞的NMDA受体的调节，包括：类型的亚基，构成一个NMDA受体，渗透的通道由Mg 2 + 0，渗透离子的受体结合，和受体功能的固有电压依赖性。我们将整合电生理，计算，分子和结构分析，以实现这些目标。该研究将加深我们对NMDA受体在广泛条件下的调节、功能和功能障碍的理解，并为深入了解NMDA受体的结构和性质之间的关系提供帮助。 相关性说明。不平衡的NMDA受体活性与许多神经系统疾病有关，包括精神分裂症、帕金森病、阿尔茨海默病、亨廷顿病、中风、癫痫、抑郁症、创伤后应激障碍和双相情感障碍。这项研究将提供对NMDA受体的更好理解，这对帮助预防和改善许多形式的脑功能障碍的后果具有巨大的潜力。

DESCRIPTION (provided by applicant): PROJECT SUMMARY. Excitatory receptors activated by the neurotransmitter L-glutamate mediate most excitatory synaptic transmission in vertebrate nervous systems. In the proposed research the glutamate receptor subtypes activated by N-methyl-D-aspartate (NMDA receptors) will be studied. NMDA receptors are essential for many basic nervous system functions, including learning and development, and are involved in a remarkable range of nervous system diseases, including numerous mental disorders. The long-term objectives of the proposed research are to understand the functional and structural properties of NMDA receptors responsible for their multiple roles in brain function. Possibly because of their involvement in multiple neural systems, NMDA receptors are subject to many forms of physiological regulation. One of the most powerful forms of regulation is block of the ion channel of NMDA receptors by extracellular magnesium ions (Mg2+o). The properties of channel block by Mg2+o are fundamental determinants of NMDA receptor involvement in brain function. Several drugs of pharmaceutical importance also block the channels of NMDA receptors. Interaction of Mg2+o and channel-blocking drugs with NMDA receptors in turn also is highly regulated. In the proposed research, we will investigate several of the mechanisms by which channel block of NMDA receptors is regulated, including: the types of subunits that constitute an NMDA receptor, permeation of the channel by Mg2+o, receptor binding of permeant ions, and inherent voltage dependence of receptor function. We will integrate electrophysiological, computational, molecular, and structural analyses to achieve these objectives. The research will deepen our understanding of NMDA receptor regulation, function, and dysfunction under a wide range of conditions, and provide insight into the relation between the structure and properties of NMDA receptors. DESCRIPTION OF RELEVANCE. Imbalanced NMDA receptor activity has been linked to many nervous system disorders, including schizophrenia, Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, epilepsy, depression, post-traumatic stress disorder, and bipolar disorder. The improved understanding of NMDA receptors that will be provided by the proposed research has enormous potential to help prevent, and ameliorate the consequences of, many forms of brain dysfunction.