Regulation of NMDAR-Mediated Synaptic Signaling

NMDAR 介导的突触信号传导的调节

• 批准号: 10346564
• 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/10346564
• 关键词: Active Biological Transport; Address; Amino Acids; Behavior; Binding; Biological Models; Caenorhabditis elegans; Cell model; Chimera organism; Clinical; Crystallization; Data; Development; Disease; Drosophila genus; Exhibits; Foundations; 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 structure; 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; base; chemical genetics; experimental study; in vivo; insight; nervous system disorder; neural circuit; new therapeutic target; novel; novel therapeutics; optogenetics; overexpression; postsynaptic; presynaptic; protein protein interaction; receptor; relating to nervous system; 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，第一个确定的NMDAR特异性辅助蛋白，我们最近在A中发现了这一点 NMDAR介导的秀丽隐杆线虫介导的行为的修饰符的遗传筛选。 NMDAR是进化的 保守而众所周知，其在突触可塑性中的作用，即长期潜力（LTP）；他们的重要性 用于学习和记忆的蜂窝模型；以及他们直接或间接参与许多神经系统和 精神疾病。尽管NRAP-1修改了突触后NMDAR的功能，但我们表明它是 由突触前谷氨酸能神经元发布。这一发现在我们的 了解NMDAR介导的突触信号传导的调节，对控制的影响 突触强度和涉及NMDAR的某些临床疾病。在初步实验中，我们 成功获得了重组产生的NRAP-1的晶体，并确定了1.9的晶体结构 分辨率。阐明NRAP-1的结构已为NRAP-1提供重要的新见解 修改NMDAR函数。通过研究脊椎动物和秀丽隐杆线虫NMDAR，我们还证明了一个 NMDAR氨基末端域（ATD）的基本重要性 达到NRAP-1的作用机理。我们现在计划以这项基础工作为基础，询问NRAP-1如何 调节NMDAR函数的函数，即NRAP-1和NMDARS和NMDAR之间的相互作用是什么 这些相互作用如何改变受体动力学？与NMDAR的过表达相反，我们发现了 NRAP-1在体内的过表达显着增加了NMDAR介导的电流和行为。这 对控制突触可塑性具有重要意义。此外，我们发现NRAP-1是积极的 沿着神经过程运输。这些发现一起表明调节NRAP-1分泌可能 是一种用于调节活性依赖性突触强度变化的机制。因此，我们将解决 NRAP-1的运输和分泌的分子要求。我们提出的研究的相关性 之所以高，是因为NMDAR介导的信号传导的疾病与与 神经退行性疾病以及精神健康疾病（例如精神分裂症和抑郁症）。 突触分子在进化上是保守的，我们对调节机制的理解 突触信号传导大大受益于基于遗传学的无脊椎动物的研究，例如果蝇和 秀丽隐杆线。值得注意的是，NMDAR和NRAP-1样蛋白似乎已共同进化，表明脊椎动物 NMDAR可能受辅助蛋白调节。因此，我们预计我们的计划研究将有所帮助 提供一个框架，以对以蛋白质蛋白质为中心的NMDAR有新的机械理解 互动。