GLUTAMATE-GATED CHANNELS IN CENTRAL & PERIPHERAL NEURONS

中环谷氨酸门控通道

基本信息

批准号：
8469584
负责人：
James E Huettner
金额：
$ 32.09万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8469584
关键词：
AMPA Receptors Absence of pain sensation Address Affect Agonist Alzheimer&apos s Disease Arachidonic Acids Brain Cell Death Cell surface Cells Chemosensitization Clinical Cysteine Docosahexaenoic Acids Elements Epilepsy Excitatory Synapse Exhibits Exposure to Fatty Acids Funding Gated Ion Channel Generations Glutamate Receptor Glutamates Goals Intervention Ion Channel Ion Channel Gating Ischemia Kainic Acid Receptors Laboratories Learning Ligand Binding Lipid Bilayers Lipids Location Mediating Membrane Membrane Proteins Metal Ion Binding Modification Molecular Molecular Conformation N-Methyl-D-Aspartate Receptors N-Methylaspartate Names Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Neurotransmitters Nonesterified Fatty Acids Pathologic Pathology Peripheral Phenanthrolines Phospholipids Play Polyamines Predisposition Production Property Reagent Receptor Inhibition Recombinants Recovery Regulation Research Role Rotation Serum Albumin Site Synaptic Transmission Testing Therapeutic Intervention Traumatic Brain Injury Unsaturated Fatty Acids Work base brain electrical activity disulfide bond interest kainate lipid metabolism methanethiosulfonate mutant operation postsynaptic presynaptic prevent receptor research study small molecule

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of my work is to provide a better understanding of synaptic transmission by studying the operation of NMDA, AMPA and kainate receptors, which form ion channels gated by the neurotransmitter glutamate. Another major goal is to uncover properties of these receptors that may allow for clinical intervention to prevent excitotoxic cell death or to provide analgesia. The experiments in this proposal arise from several interesting discoveries that we made during the current period of support. Specific Aim 1 follows up on our observation that interactions between the pore loop and adjacent transmembrane helices govern kainate receptor susceptibility to inhibition by cis-unsaturated fatty acids, such as docosahexaenoic acid (DHA). Experiments in this aim will use mutant cycle analysis to determine which residues in the channel interact with each other to control permeation, gating and modulation. Specific Aim 2 builds on our discovery that exposure to DHA appears to change the conformation of kainate receptor transmembrane helices in the open state. Reactivity of substituted cysteines, metal ion binding, and disulfide bond formation will be used to determine structural changes introduced by fatty acids. Specific Aim 3 follows up on our discovery of small molecule antagonists that prevent DHA from potentiating NMDA receptors but have little or no effect on DHA inhibition of kainate receptors. Chimeric subunits that combine domains from NMDA and kainate receptors will be used to investigate whether distinct structural interactions underlie the potentiation and inhibition of channel activity and t analyze the structural requirements for generation of functional channels. Collectively, these experiments will provide new information about the structural basis for ionotropic glutamate receptor operation and new information about how ion channels are affected by interactions with components of the lipid bilayer. A number of pathologic conditions, including brain trauma, epilepsy, and ischemia, elicit massive release of cis-unsaturated fatty acids. These compounds directly regulate many different membrane proteins including a number of ion channel subtypes. This project analyzes the molecular basis of glutamate receptor modulation by DHA, which is present at high levels in the nervous system and is known to be essential for normal brain function.

描述（由申请人提供）：我工作的长期目标是通过研究NMDA，AMPA和海藻酸盐受体的运行来更好地理解突触传播，该操作形成了由神经递质谷氨酸的离子通道。另一个主要目标是发现这些受体的特性，这些受体可能允许临床干预以防止兴奋性细胞死亡或提供镇痛。该提案中的实验来自我们在当前支持期间做出的一些有趣的发现。具体目的1遵循我们的观察结果，即孔环与邻近跨膜螺旋之间的相互作用控制着海藻酸盐受体受体易感性对顺式不饱和脂肪酸的抑制作用，例如docosahexaenoic（DHA）。此目标中的实验将使用突变循环分析来确定通道中的哪些残基相互作用以控制渗透，门控和调节。具体目标2基于我们发现，暴露于DHA似乎改变了开放状态下海藻酸盐受体跨膜螺旋的构象。取代的半胱氨酸，金属离子结合和二硫键形成的反应性将用于确定脂肪酸引入的结构变化。特定目标3遵循我们发现的小分子拮抗剂，这些拮抗剂可防止DHA增强NMDA受体，但对Kainate受体的抑制作用几乎没有影响。结合NMDA和海藻酸盐受体结构域的嵌合亚基将用于研究是否在通道活性的增强和抑制基础上，分析了功能通道产生的结构要求。总的来说，这些实验将提供有关离子谷氨酸受体操作的结构基础的新信息，以及有关离子通道如何受到与脂质双层组件相互作用的影响的新信息。许多病理状况，包括脑外伤，癫痫和缺血，引起顺式不饱和脂肪酸的大规模释放。这些化合物直接调节许多不同的膜蛋白，包括许多离子通道亚型。该项目通过DHA分析了谷氨酸受体调节的分子基础，DHA在神经系统中的高水平存在，已知对于正常的脑功能至关重要。