The Physiology of Store-Operated Channels in the Nervous System

神经系统中存储操纵通道的生理学

• 批准号: 10672816
• 负责人: Murali Prakriya
• 金额: $ 83.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2031-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672816
• 关键词: Address; Architecture; Astrocytes; Behavioral; Brain; Brain Diseases; Brain Pathology; Calcium; Calcium Channel; Cell membrane; Cells; Cognition; Communication; Dependence; Disease; Electrophysiology (science); Endoplasmic Reticulum; Etiology; Exhibits; Gene Expression; Genetic Transcription; Goals; Immune; Immunologic Deficiency Syndromes; Inflammation; Ion Channel; Knockout Mice; Learning; Mediating; Memory; Mental Depression; Metabolism; Modeling; Molecular; Myopathy; Nervous System; Neuroglia; Neurons; Neurotransmitters; Pain; Pathway interactions; Physiological; Physiology; Process; Property; Protein Isoforms; Receptor Signaling; Regulation; Role; STIM1 gene; Signal Pathway; Signal Transduction; Site; Synapses; Synaptic plasticity; Work; cytokine; drug discovery; insight; member; molecular dynamics; nervous system disorder; neurotransmitter release; new therapeutic target; nuclear factors of activated T-cells; painful neuropathy; sensor

Project Summary Ca2+ signaling mediates many essential roles in the brain including neurotransmitter release, synaptic plasticity, and gene transcription. Neurons and glia have an extensive Ca2+ signaling toolkit that includes many types of ion channels and Ca2+ release pathways which can be mixed and matched to create signals with widely different spatial and temporal properties. One of the newest - and least understood - members of this toolkit in the brain is store-operated calcium entry (SOCE). SOCE is mediated by the opening of Orai channels (Orai1-3), which are activated by the endoplasmic reticulum Ca2+ sensors, STIM1 and STIM2. In immune cells where SOCE was first discovered, the pathway mediates critical functions including gene expression and cytokine release, and aberrant Orai/STIM function is implicated in the etiology of several diseases including immunodeficiency, inflammation, and myopathy. However, in the brain where multiple isoforms of Orai and STIM are expressed, the molecular mechanisms and physiological functions of SOCE remain very poorly understood. Previous work on the molecular choreography of SOCE has revealed that Orai channel opening is triggered by a unique inside-out mechanism where store depletion activates the ER Ca2+ sensors STIM1 and STIM2 which then translocate to ER-plasma membrane contact sites to directly gate Orai1 channels. Our previous mechanistic work has established a strong framework for understanding the gating mechanisms of Orai channels, and using conditional Orai1 and STIM1 knockout mice, we have now begun to discover vital roles for Orai channels in effector functions in the brain such as NFAT-mediated gene expression, synaptic plasticity, and memory. We have learnt that SOCE in neurons exhibits unique specializations, including rapid activation and unusual Ca2+ dependencies whose basis cannot be readily explained easily from existing activation models. In this application, we aim to build an integrated view of the SOCE mechanism in the nervous system, its micro and macro architecture, regulation, and gating, and elucidate how neurotransmitter and receptor signaling through SOCE impacts fundamental processes of synaptic communication, metabolism, learning, and cognition. To address this goal, we will use a full range of approaches from electrophysiology, structural analysis, and molecular dynamics simulations to behavioral analysis of cognition, depression, and disease to gain an unprecedented view of the SOCE mechanism in the brain. These studies will address the role of a poorly understood Ca2+ entry pathway in the nervous system with immense relevance for a range of functions from cognition to pain, and ultimately facilitate efforts to target Orai channels for drug discovery for neurological diseases.

项目概要 Ca2+ 信号传导介导大脑中的许多重要作用，包括神经递质释放、突触 可塑性和基因转录。神经元和神经胶质细胞具有广泛的 Ca2+ 信号传导工具包，其中包括 多种类型的离子通道和 Ca2+ 释放途径，可以混合和匹配以创建 具有截然不同的空间和时间特性的信号。最新且最不被理解的之一 - 这个工具包的成员是大脑中的钙离子储存库（SOCE）。 SOCE 是由 打开由内质网 Ca2+ 传感器激活的 Orai 通道 (Orai1-3)， STIM1 和 STIM2。在首次发现 SOCE 的免疫细胞中，该途径介导关键的 功能包括基因表达和细胞因子释放，并且涉及异常的 Orai/STIM 功能 多种疾病的病因学，包括免疫缺陷、炎症和肌病。然而， 在表达 Orai 和 STIM 多种亚型的大脑中，分子机制和 SOCE 的生理功能仍然知之甚少。之前的分子研究工作 SOCE的编排揭示了Orai通道的打开是由独特的由内而外触发的 储存耗尽激活 ER Ca2+ 传感器 STIM1 和 STIM2 的机制，然后 易位至 ER 质膜接触位点以直接门控 Orai1 通道。我们之前的 机械工作为理解 Orai 的门控机制建立了强大的框架 通道，并使用条件性 Orai1 和 STIM1 基因敲除小鼠，我们现在已经开始发现至关重要的 Orai 通道在大脑效应功能中的作用，例如 NFAT 介导的基因表达， 突触可塑性和记忆。我们了解到神经元中的 SOCE 表现出独特的专业性， 包括快速激活和不寻常的 Ca2+ 依赖性，其基础无法轻易解释 可以轻松地从现有的激活模型中获得。在此应用程序中，我们的目标是构建一个集成视图 神经系统中的 SOCE 机制，其微观和宏观结构、调节和门控，以及 阐明通过 SOCE 的神经递质和受体信号传导如何影响基本过程 突触通讯、新陈代谢、学习和认知。为了实现这一目标，我们将使用完整的 电生理学、结构分析和分子动力学模拟等一系列方法 对认知、抑郁和疾病进行行为分析，以获得对 SOCE 的前所未有的了解 大脑中的机制。这些研究将解决人们对 Ca2+ 进入途径知之甚少的作用 在神经系统中与从认知到疼痛的一系列功能密切相关，并且 最终促进针对 Orai 通道的神经系统疾病药物发现的努力。