Gating and permeation in ionotropic glutamate receptors

离子型谷氨酸受体的门控和渗透

基本信息

批准号：
8886217
负责人：
LONNIE P WOLLMUTH
金额：
$ 34.14万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8886217
关键词：
AMPA Receptors Acute Address Affect Agonist Allosteric Site Beryllium Binding Biological Assay Brain Brain Diseases Charge Chronic Cysteine Development Disease Drug Design Dyes Elements Encephalopathies Epilepsy Gated Ion Channel Glutamate Receptor Glutamates Goals Human Inherited Internet Ion Channel Ions Knowledge Learning Ligand Binding Domain Maps Measures Mediating Missense Mutation Molecular Mutation N-Methyl-D-Aspartate Receptors Nervous System Physiology Nervous system structure Neurodevelopmental Disorder Neurotransmitter Receptor Neurotransmitters Outcome Pathway interactions Peripheral Pharmaceutical Preparations Physiological Physiology Positioning Attribute Property Receptor Activation Resolution Schizophrenia Signal Transduction Site Societies Specificity Steroids Structure Synapses Synaptic Transmission Thermodynamics Translating Variant channel blockers clinically significant crosslink developmental disease disease-causing mutation driving force drug of abuse excitotoxicity mind control mutant nervous system disorder neurotransmission neurotransmitter release operation polypeptide postsynaptic presynaptic public health relevance receptor receptor function research study response therapy development

项目摘要

DESCRIPTION (provided by applicant): The overall goal of my efforts is to define molecular features of synaptic transmission in the nervous system by studying the operation of NMDA and AMPA receptors. These receptors are neurotransmitter-gated ion channels that convert the presynaptic release of glutamate, the predominant excitatory neurotransmitter in the brain, into a postsynaptic signal. By defining the operation of NMDA and AMPA receptors, we will gain a better understanding of how they control brain function. We will also learn how to modulate their function with greater precision and specificity to help understand, and potentially treat, disease states such as schizophrenia, epilepsy, and the excitotoxicity associated with acute and chronic brain disorders. Our experiments will focus on structural elements of the NMDA and AMPA receptor located to the periphery of those lining the permeation pathway of the ion channel. Recent evidence has indicated that inherited and de novo mutations in these outer or peripheral structures induce developmental disorders and epileptic encephalopathies. These outer structures also contain allosteric sites for drugs of abuse and are targets for newly developed NMDA receptor modulators. Aim 1 will address the impact of the outer structures to the rapid and efficient pore opening that is the hallmark of fast synaptic transmission. For these experiments, we will combine single channel recordings with non-equilibrium conditions to define the energetics of displacement of the outer structures. Aim 2 will address how permeant ions access the central permeation pathway through the outer structures. Aim 3 will address how disease- causing mutations interact at the outer structures to alter NMDA and AMPA receptor function. Here, we will use cysteine cross-linking, fast agonist application, and agonist-free single channel recordings to address how specific elements interact in the outer structures to modulate receptor function. Overall our experiments will delineate how the outer structures contribute to the operation of NMDA and AMPA receptors. This information will aid in defining how disease-causing mutations affect receptor function and in developing specific therapies to target these receptors in nervous system disorders.

描述（由申请人提供）：我努力的总体目标是通过研究 NMDA 和 AMPA 受体的运作来定义神经系统中突触传递的分子特征。这些受体是神经递质门控离子通道，可转换谷氨酸的突触前释放。大脑中主要的兴奋性神经递质转化为突触后信号通过定义 NMDA 和 AMPA 受体的运作，我们将获得更好的理解。我们还将学习如何更精确和特异性地调节它们的功能，以帮助理解和潜在地治疗精神分裂症、癫痫以及与急性和慢性脑部疾病相关的兴奋性毒性等疾病。将重点关注位于离子通道渗透途径外围的 NMDA 和 AMPA 受体的结构元件，最近的证据表明这些外部或外围结构中的遗传和从头突变会诱导发育。这些外部结构还包含滥用药物的变构位点，并且是新开发的 NMDA 受体调节剂的目标，目标 1 将解决外部结构对快速有效的孔开放的影响，这是快速突触的标志。对于这些实验，我们将结合单通道记录和非平衡条件来定义外部结构的位移能量学，目标 2 将解决渗透离子如何进入中心。目标 3 将解决外部结构中致病突变如何相互作用以改变 NMDA 和 AMPA 受体功能。在这里，我们将使用半胱氨酸交联、快速激动剂应用和无激动剂单一。总体而言，我们的实验将描述外部结构如何促进 NMDA 和 AMPA 受体的运作，这些信息将有助于确定如何引起疾病。影响受体功能并开发针对神经系统疾病中这些受体的特定疗法。