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Structure and Function of native kainate-type ionotropic glutamate receptor complexes

天然红藻氨酸型离子型谷氨酸受体复合物的结构和功能

基本信息

批准号：
10798368
负责人：
NAMI TAJIMA
金额：
$ 9.75万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-05 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10798368
关键词：
Alzheimer&apos s Disease Brain Brain Diseases Cholesterol Complex Cryoelectron Microscopy Development Distant Drug Targeting Electrophysiology (science)Environment Epilepsy Exhibits Functional disorder Future Glutamate Receptor Homo Huntington Disease Kainic Acid Receptors Learning Ligands Lipids Major Depressive Disorder Mediating Memory Modification Molecular Molecular Conformation Mood Disorders Neurons Neuropilins Physiological Play Post-Translational Protein Processing Property Proteins Rattus Regulation Research Resolution Role Schizophrenia Signal Transduction Structure Synapses Synaptic Transmission Synaptic plasticity autism spectrum disorder cofactor glutamatergic signaling insight interest kainate neural neuronal excitability neuropathology neurotransmitter release novel novel therapeutic intervention pharmacologic postsynaptic programs receptor receptor function small molecule therapy development treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Neuronal ionotropic glutamate receptors (iGluRs) play key roles in mediating excitatory synaptic transmission in the brain and in a wide range of brain diseases, including Alzheimer’s and Huntington’s disease, schizophrenia, epilepsy, autism spectrum, major depression, and mood disorders. Glutamatergic signaling is pivotal for synaptic plasticity, learning, and memory formation. Kainate-type ionotropic glutamate receptors (KARs) are distributed throughout the brain and regulate the release of neurotransmitters and mediate excitatory synaptic transmission. KARs form homo- or hetero-tetramers composed of five homologous subunits of GluK1–5. Each subunit exhibits unique structural, functional, and pharmacological properties and subcellular localization. Moreover, misguided localization and dysfunction of KARs result in neuropathologies, therefore, KARs are a promising drug target. However, KARs are the least well understood group of iGluRs, and their molecular mechanisms remain elusive. The activities of neuronal KARs are regulated by pH, posttranslational modifications, lipid/cholesterol, and small molecules. Additionally, KAR function and localization are further modified by their auxiliary and accessory proteins. Thus, such brain lipids, modifications, and protein co-factors increase the diversity of KAR functional properties. The neuropilin and tolloid-like (NETO) auxiliary proteins, NETO1 and NETO2, are auxiliary proteins of KARs that are distantly homologous compared with auxiliary proteins associated with other iGluRs. How do such ligands and protein co-factors determine the gating of KARs and regulate synaptic signaling? How are the physiological brain lipid environment and posttranslational modifications contributing to receptor activities? To answer these questions, this proposed research will employ structural and electrophysiological approaches to develop our mechanistic understanding of the regulation of native postsynaptic GluK2/GluK5 KARs isolated from rat brains. The program will move forward in two major directions: In one project, I will determine high-resolution cryo-electron microscopy (cryo-EM) structures of native GluK2/GluK5 KARs in an activated state, but also in complex with ligands to capture multiple functional states. This will elucidate the conformational alternations of GluK2/GluK5 KARs by their ligands, which have not been well-observed in previously determined structures. Comparing our structures with other iGluRs will uncover how physiologically relevant heteromeric KARs are structurally and functionally distinct from other iGluR subfamilies. In a second concurrent project, we will elucidate the regulatory mechanisms of native KARs by NETO1 and NETO2 auxiliary proteins. Overall, our studies will provide fundamental insights into how neuronal KAR complexes are controlled by their ligands and auxiliary proteins, and how they mediate synaptic signaling, and thus neural activities. This information will facilitate the development of new therapeutic strategies for treating brain diseases.

项目摘要/摘要神经元性谷氨酸受体在介导兴奋性突触传递中起关键作用大脑和各种脑部疾病，包括阿尔茨海默氏症和亨廷顿氏症，精神分裂症，癫痫、自闭症谱系、严重抑郁和情绪障碍。谷氨酸能信号对突触起关键作用可塑性、学习和记忆的形成。海藻酸型离子型谷氨酸受体(KARs)的分布并调节神经递质的释放，调节兴奋性突触传递。 KARs形成由GluK1-5的五个同源亚基组成的同源或异源四聚体。每个亚基都有独特的结构、功能和药理特性以及亚细胞定位。此外，误入歧途 KARS的定位和功能障碍导致了神经病理，因此KARS是一个很有前途的药物靶点。然而，KARs是最不为人所知的iGluR基团，其分子机制仍然难以捉摸。神经元KARs的活性受pH、翻译后修饰、脂质/胆固醇和小分子分子。此外，KAR的功能和本地化还被它们的辅助和附件进一步修改蛋白质。因此，这种脑脂类物质、修饰和蛋白质辅助因子增加了KAR功能的多样性。属性。NETO1和NETO2是神经粘连蛋白和类TOLO辅助蛋白的辅助蛋白与与其他iGluR相关的辅助蛋白相比具有较远同源性的KARs。做什么这种配体和蛋白质共因子决定了KARs的门控并调节突触信号？孩子们怎么样了？生理性脑脂环境和翻译后修饰对受体活性的影响？至回答这些问题，这项拟议的研究将使用结构和电生理方法来发展我们对分离的天然突触后GluK2/GluK5 Kars调节的机械理解老鼠的大脑。该计划将朝着两个主要方向前进：在一个项目中，我将确定高分辨率天然GluK2/GluK5 Kars的低温电子显微镜(Cryo-EM)结构与配体形成的络合物，以捕捉多种功能状态。这将阐明分子的构象变化 GluK2/GluK5 Kars通过它们的配体，这在以前确定的结构中还没有被很好地观察到。将我们的结构与其他iGluR进行比较，将会发现KAR在生理上是多么相关在结构和功能上与其他iGluR亚家族截然不同。在第二个并行项目中，我们将阐明NETO1和Neto2辅助蛋白对天然KARs的调控机制。总的来说，我们的研究将为神经元KAR复合体如何受其配体和辅助蛋白，以及它们如何调节突触信号，从而影响神经活动。此信息将促进开发治疗脑部疾病的新治疗策略。