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Synaptic targeting and regulation of NMDAR subunits

NMDAR 亚基的突触靶向和调节

基本信息

批准号：
9039662
负责人：
John Alan Gray
金额：
$ 18.08万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039662
关键词：
Address Alzheimer&apos s Disease Binding Biochemical Brain C-terminal Chronic Clinical Cognitive Complex Data Development Disease Dissection Electrophysiology (science)Endocytosis Excision Functional disorder Genetic Goals Gray unit of radiation dose Health Hippocampus (Brain)Image Individual Institution Ischemic Stroke K-Series Research Career Programs Knockout Mice Laboratory Research Lead Ligands Literature Mediating Mental Depression Mentors Modeling Molecular Molecular and Cellular Biology N-Methyl-D-Aspartate Receptors NMDA receptor A1 Nature Neurocognitive Neurons Neurosciences Pathway interactions Pharmacology Phosphorylation Phosphotyrosine Physiology Play Postdoctoral Fellow Process Property Prosencephalon Proteins Proteomics Psychiatrist Recombinants Regulation Research Resistance Role Schizophrenia Scientist Slice Structure Surface Symptoms Synapses Synaptic plasticity TFAP2A gene Tail Therapeutic Training Tyrosine Tyrosine Phosphorylation addiction density frontier genetic approach improved innovation insight neurodevelopment neuropsychiatric disorder novel novel therapeutics programs protein protein interaction receptor receptor function src-Family Kinases synaptic function theories trafficking

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this research program is to better understand the molecular mechanisms by which N-methyl-D-aspartate receptors (NMDARs) are regulated to modulate synapse development and synaptic plasticity, and how these processes might be disrupted in complex neuropsychiatric disorders such as schizophrenia. The applicant for this K08 Mentored Clinical Scientist Research Career Development Award, Dr. John Gray, is a psychiatrist and a postdoctoral fellow with Dr. Roger Nicoll at UCSF. Dr. Gray's long-term research goals are to lead an independent research laboratory in psychiatric neuroscience at an academic institution combining cellular, molecular, electrophysiological, and genetic approaches to study synapse function with the goal of understanding how disruptions of the normal mechanisms of synapse development might underlie the pathophysiology of major neuropsychiatric disorders. Though etiological mechanisms underlying schizophrenia remain largely unknown, a convergence of pharmacologic and genetic data implicates a dysregulation of NMDAR function. NMDARs play critical roles in neurodevelopment and synaptic plasticity and subtle changes in NMDAR functioning can have wide-ranging developmental and cognitive effects. Most forebrain NMDARs contain two GluN1 and two GluN2A or GluN2B subunits, with receptor trafficking and functional properties largely dictated by the GluN2 subunit composition. Until recently the dogma in the field was that NMDARs were relatively immobile fixed structures, though it is now apparent that there is a remarkable plasticity of synaptic NMDARs. Indeed, the expression, trafficking, synaptic localization and functioning of different NMDARs subtypes are under dynamic cellular control, though the mechanisms are poorly understood. In this research plan, the roles of GluN2 subunit C-terminal tails in NMDAR synaptic targeting, trafficking, and regulation will be systematically investigated using an innovative molecular replacement approach in which native NMDARs are removed and replaced by recombinant NMDAR subunits in individual neurons. By combining his training in molecular and cellular biology, receptor pharmacology, and synaptic electrophysiology, Dr. Gray will pursue additional training in biochemical and proteomic analysis to address the following specific aims: 1) to determine the role of GluN2B-S1480 phosphorylation in NMDAR trafficking; 2) to determine the mechanism of GluN2A targeting to synapses; and 3) to determine the role of tyrosine phosphorylation in NMDAR trafficking and regulation. Successful completion of this proposal will identify novel trafficking mechanisms, new targeting motifs and new proteins important in NMDAR regulation and synaptic development and plasticity and will open new frontiers for the development of disease-modifying therapeutic approaches for schizophrenia and other neuropsychiatric disorders.

描述（由申请人提供）：该研究项目的总体目标是更好地了解 N-甲基-D-天冬氨酸受体 (NMDAR) 调节突触发育和突触可塑性的分子机制，以及这些过程如何在精神分裂症等复杂的神经精神疾病中被破坏。 K08 指导临床科学家研究职业发展奖的申请人 John Gray 博士是一名精神病学家，也是加州大学旧金山分校 Roger Nicoll 博士的博士后研究员。格雷博士的长期研究目标是在一个学术机构领导一个精神神经科学的独立研究实验室，结合细胞、分子、电生理学和遗传学方法来研究突触功能，目的是了解突触发育正常机制的破坏如何可能成为主要神经精神疾病病理生理学的基础。尽管精神分裂症的病因机制在很大程度上仍不清楚，但药理学和遗传数据的融合表明 NMDAR 功能失调。 NMDAR 在神经发育和突触可塑性中发挥着关键作用，NMDAR 功能的细微变化可能会产生广泛的发育和认知影响。大多数前脑 NMDAR 包含两个 GluN1 和两个 GluN2A 或 GluN2B 亚基，受体运输和功能特性很大程度上取决于 GluN2 亚基组成。直到最近，该领域的教条还认为 NMDAR 是相对不可移动的固定结构，尽管现在很明显突触 NMDAR 具有显着的可塑性。事实上，不同 NMDAR 亚型的表达、运输、突触定位和功能都处于动态细胞控制之下，尽管其机制尚不清楚。在该研究计划中，将使用创新的分子替换方法系统地研究 GluN2 亚基 C 末端尾部在 NMDAR 突触靶向、运输和调节中的作用，其中天然 NMDAR 被去除并被单个神经元中的重组 NMDAR 亚基替换。通过结合分子和细胞生物学、受体药理学和突触电生理学方面的培训，Gray 博士将继续接受生化和蛋白质组分析方面的额外培训，以实现以下具体目标：1) 确定 GluN2B-S1480 磷酸化在 NMDAR 运输中的作用； 2) 确定GluN2A靶向突触的机制； 3) 确定酪氨酸磷酸化在 NMDAR 运输和调节中的作用。该提案的成功完成将确定在 NMDAR 调节以及突触发育和可塑性中重要的新转运机制、新靶向基序和新蛋白质，并将为开发精神分裂症和其他神经精神疾病的疾病缓解治疗方法开辟新领域。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GluN3A subunit tunes NMDA receptor synaptic trafficking and content during postnatal brain development.

GluN3A 亚基在出生后大脑发育过程中调节 NMDA 受体突触运输和内容。

DOI：
10.1016/j.celrep.2023.112477
发表时间：
2023
期刊：
Cell reports
影响因子：
8.8
作者：
González-González,InmaculadaM;Gray,JohnA;Ferreira,Joana;Conde-Dusman,MaríaJose;Bouchet,Delphine;Perez-Otaño,Isabel;Groc,Laurent
通讯作者：
Groc,Laurent

Activated CaMKII couples GluN2B and casein kinase 2 to control synaptic NMDA receptors.