Regulation of NMDAR-Mediated Synaptic Signaling

NMDAR 介导的突触信号传导的调节

• 批准号: 10533340
• 负责人: Andres Villu Maricq
• 金额: $ 52.85万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533340
• 关键词: Active Biological Transport; Amino Acids; Behavior; Binding; Biological Models; Caenorhabditis elegans; Cell model; Chimera organism; Clinical; Data; Development; Disease; Drosophila genus; Exhibits; Genes; Genetic; Genetic Screening; Genetic Techniques; Glutamate Receptor; Glutamates; Goals; Homologous Gene; Invertebrates; Kinetics; Learning; Long-Term Potentiation; Maps; Mediating; Memory; Mental Depression; Mental Health; Mental disorders; Modality; Modeling; Molecular; Molecular Motors; Mutation; N-Methylaspartate; Nervous System; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Neurotransmitters; Process; Proteins; Recombinants; Regulation; Research; Resolution; Role; Scaffolding Protein; Schizophrenia; Signal Transduction; Site; Structure; Synapses; Synaptic plasticity; Testing; Transgenic Organisms; Work; chemical genetics; experimental study; in vivo; insight; nervous system disorder; neural; neural circuit; new therapeutic target; novel; novel therapeutics; optogenetics; overexpression; postsynaptic; presynaptic; protein protein interaction; receptor; synaptic function

PROJECT SUMMARY/ABSTRACT We propose to study the NMDA-subtype (NMDARs) of ionotropic glutamate receptors (iGluRs) and their regulation by NRAP-1, the first identified NMDAR-specific auxiliary protein, which we recently discovered in a genetic screen for modifiers of NMDAR-mediated behavior in C. elegans. NMDARs are evolutionarily conserved and well known for their role in synaptic plasticity, i.e., long-term potentiation (LTP); their importance for cellular models of learning and memory; and their direct or indirect involvement in many neurological and psychiatric disorders. Although NRAP-1 modifies the function of postsynaptic NMDARs, we showed that it was released by presynaptic glutamatergic neurons. This discovery provided a major conceptual advance in our understanding of the regulation of NMDAR-mediated synaptic signaling, with implications for both the control of synaptic strength and for certain clinical disorders involving NMDARs. In preliminary experiments, we successfully obtained crystals of recombinantly produced NRAP-1 and determined the crystal structure at 1.9 Å resolution. Elucidating the structure of NRAP-1 has provided important new insight into how NRAP-1 modifies NMDAR function. By studying vertebrate and C. elegans NMDARs, we have also demonstrated a fundamental importance for the NMDAR amino-terminal domain (ATD) with respect to both receptor gating and to the mechanism of action of NRAP-1. We now plan to build on this foundational work and ask how NRAP-1 functions to modulate NMDAR function, i.e., what are the interactions between NRAP-1 and NMDARs, and how do these interactions change receptor kinetics? In contrast to overexpression of NMDARs, we discovered that overexpression of NRAP-1 in vivo significantly increased NMDAR-mediated currents and behavior. This has important implications for the control of synaptic plasticity. Furthermore, we found that NRAP-1 is actively transported along neural processes. Together, these findings suggest that modulating NRAP-1 secretion might be a mechanism used to regulate activity dependent changes in synaptic strength. Therefore, we will address the molecular requirements for the transport and secretion of NRAP-1. The relevance of our proposed studies is high because disorders of NMDAR-mediated signaling are implicated in synaptopathies associated with neurodegenerative disorders as well as for mental health illnesses such as schizophrenia and depression. Synaptic molecules are evolutionarily conserved, and our understanding of the mechanisms that regulate synaptic signaling has greatly benefited from genetics-based studies in invertebrates such as Drosophila and C. elegans. Notably, NMDARs and NRAP-1-like proteins appear to have co-evolved suggesting that vertebrate NMDARs are likely regulated by auxiliary proteins. We therefore anticipate that our planned studies will help provide a framework for a new mechanistic understanding of NMDARs centered on protein-protein interactions.

项目摘要/摘要 我们建议研究离子型谷氨酸受体（iGlurs）及其其NMDA-SUBTYPE（NMDAR）及其 NRAP-1的调节，即首个NMDAR特异性辅助蛋白，我们最近在A中发现 NMDAR介导的行为的遗传筛选在C.进化中。 保守和众所周知，它们在突触可塑性中的作用，即长期潜力（LTP）； 用于学习和记忆的细胞模型及其直接或间接介入 精神病障碍。 由突触前谷氨酸神经元发行。 了解NMDAR介导的突触信号传导的调节，对控制的影响 突触强度和某些临床疾病涉及NMDARS。 成功获得了综合产生的NRAP-1的晶体，并确定了1.9的晶体结构 Å分辨率。 通过研究脊椎动物和秀丽隐杆线虫NMDARS修改NMDAR功能 NMDAR氨基末端域（ATD）的基本重要性 对于NRAP-1的作用机制，我们现在计划以基础工作为基础 模块NMDAR函数的函数，即NRAP-1和NMDARS和NMDARS和 这些相互作用如何改变受体动力学？ NRAP-1在体内的过表达显着增加了NMDAR介导的电流和行为。 对控制突触塑料具有重要意义。 沿着神经过程运输。 是一种用于调节活性依赖性突触强度变化的机制。 NRAP-1的运输和分泌的分子要求。 之所以很高，是因为NMDAR介导的信号传导的疾病与与之相关的突触病涉及。 神经退行性疾病以及精神健康疾病（例如精神分裂症和剥夺）。 突触分子在进化上是保守的，我们对调节机制的理解 突触信号传导受益于基于遗传学的无脊椎动物的研究，例如果蝇和和 秀丽隐杆线虫。 NMDAR可能受辅助蛋白的调节。 提供一个框架，以对以蛋白质蛋白质为中心的NMDAR产生新的机械理解 互动。