Interaction of Ions with NMDA Receptors

描述（由申请人提供）：由 神经递质L-谷氨酸负责大多数快速兴奋性突触 脊椎动物神经系统中的交流。在拟议的研究中， N-甲基-D-天冬氨酸特异性激活的谷氨酸受体亚型 (NMDA受体）进行研究。NMDA受体是许多基本的 神经系统的功能，包括发育和记忆的形成。 NMDA受体活性失衡与许多神经系统 包括精神分裂症、帕金森病、阿尔茨海默病， 亨廷顿舞蹈病、中风和癫痫。离子的独特性质 NMDA受体形成的通道是必不可少的，因为它在 神经系统功能和功能障碍。的长期目标 建议的研究是了解离子通道的结构和性质 对NMDA受体功能至关重要。 NMDA受体受到多种形式的生理调节。之一 最有效的是阻断NMDA受体的离子通道， 胞外镁离子（Mg约）。Mg~（2+）的阻断作用则是强的 受细胞外和细胞内离子的调节，这些离子可以渗透到 NMDA受体通道。为了实现拟议研究的目标， 具体目标如下：（1）研究如何使 调节离子Ca2+影响Mg2+对NMDA受体通道的阻断（2） 确定渗透性离子对Mg2+阻断的影响在NMDA中如何变化 受体亚型;（3）鉴定NMDA结构中的氨基酸 参与形成渗透离子结合位点的受体， 这些目标将通过以下组合来实现： 来自细胞和单个NMDA受体的电生理记录， NMDA受体活性的计算机建模，以及对 NMDA受体结构的分子生物学方法。结果 建议的研究将扩展我们对结构的理解， NMDA受体的运作，从而提供深入了解他们的运作， 神经系统生理学和疾病。

DESCRIPTION (provided by applicant): Excitatory receptors activated by the neurotransmitter L-glutamate are responsible for most fast excitatory synaptic communication in vertebrate nervous systems. In the proposed research the glutamate receptor subtypes specifically activated by N-methyl-D-aspartate (NMDA receptors) will be studied. NMDA receptors are required for many basic functions of the nervous system, including development and memory formation. Imbalanced NMDA Receptor activity has been linked to numerous nervous system disorders, including schizophrenia, Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, and epilepsy. The unique properties of the ion channel formed by NMDA receptors are essential for its central position in nervous system function and dysfunction. The long-term objectives of the proposed research are to understand the ion channel structures and properties that are about central to NMDA receptor function. NMDA receptors are subject to many forms of physiological regulation. One of the most powerful is block of the ion channel of NMDA receptors by extracellular magnesium ions (Mg about). Block by Mg2+ in turn is strongly regulated by both extracellular and intracellular ions that can permeate the channel of NMDA receptors. To achieve he objectives of the proposed research, the following specific aims will be pursued: (1) examine how the important regulatory ion Ca2+ affects block of the channel of NMDA receptors by Mg2+ (2) determine how the effect of permeant ions on Mg2+ block varies among NMDA receptor subtypes; (3) identify amino acids within the structure of NMDA receptors that are involved in forming the site at which permeant ions bind and affect block by Mg2+ These aims will be achieved through a combination of electrophysiological recording from cells and from single NMDA receptors, computational modeling of NMDA receptor activity, and manipulation of the structure of NMDA receptors using molecular biological approaches. The results of the proposed research will extend our understanding of the structure and operation of NMDA receptors, and thus provide insight into their operation in nervous system physiology and disease.