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.

项目摘要 Ca 2+信号在脑中介导许多重要作用，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有一个广泛的Ca 2+信号工具包，包括 许多类型的离子通道和Ca 2+释放途径，可以混合和匹配， 具有广泛不同的空间和时间特性的信号。一个最新的，也是最不为人所知的 - 大脑中这个工具包的成员是钙库操作的钙进入（SOCE）。SOCE是由 开放奥赖通道（Orai 1 -3），其由内质网Ca 2+传感器激活， STIM 1和STIM 2。在首次发现SOCE的免疫细胞中，该途径介导了关键的 包括基因表达和细胞因子释放的功能，以及异常的奥赖/STIM功能涉及 在免疫缺陷、炎症和肌病等多种疾病的病因学中的作用。然而，在这方面， 在表达奥赖和STIM多种亚型的脑中， SOCE的生理功能仍然知之甚少。以前的工作在分子 SOCE的编排揭示了奥赖通道的开放是由一种独特的由内而外的 储存耗尽激活ER Ca 2+传感器STIM 1和STIM 2的机制， 转移到ER-质膜接触位点以直接门控Orai 1通道。我们以前的 机械工作建立了一个强有力的框架，以了解奥赖的门控机制 通道，并使用条件Orai 1和STIM 1敲除小鼠，我们现在已经开始发现重要的 奥赖通道在脑中效应子功能如NFAT介导的基因表达中的作用， 突触可塑性和记忆。我们已经了解到，神经元中的SOCE表现出独特的专业化， 包括快速激活和不寻常的Ca 2+依赖性，其基础无法轻易解释 很容易从现有的激活模型。在这个应用程序中，我们的目标是建立一个集成的视图， 神经系统中的SOCE机制，其微观和宏观结构，调节和门控，以及 阐明神经递质和受体信号如何通过SOCE影响基本过程 突触通讯、新陈代谢、学习和认知的过程。为了实现这一目标，我们将使用 从电生理学、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的前所未有的看法。 大脑中的机制。这些研究将解决一个知之甚少的Ca 2+进入途径的作用 在神经系统中与从认知到疼痛的一系列功能有着巨大的相关性， 最终促进了针对奥赖渠道的努力，用于神经系统疾病的药物发现。