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+)信号在脑内介导许多重要作用，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丰富的钙信号工具包，包括 多种类型的离子通道和钙离子释放途径，可以混合和匹配以创建 具有非常不同的空间和时间特性的信号。最新的--也是最不为人所知的 -大脑中这个工具包的成员是商店操作的钙输入(SOCE)。SOCE由 开放由内质网钙感受器激活的Orai通道(Orai1-3)， STIM1和STIM2。在最早发现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在内的功能，以及异常的Orai/STIM功能 在几种疾病的病因学上，包括免疫缺陷、炎症和肌病。然而， 在表达多种Orai和STIM亚型的大脑中，分子机制和 SOCE的生理功能仍然知之甚少。关于分子的先前工作 SOCE的编排揭示了Orai通道的打开是由一个独特的内向外触发的 存储器耗尽激活内质网钙离子传感器STIM1和STIM2的机制 转移到内质网-质膜接触部位，直接门控Orai1通道。我们以前的 机械论工作为理解Orai的门控机制建立了一个强有力的框架 渠道，并使用条件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通道在大脑效应器功能中的作用，如NFAT介导的基因表达， 突触可塑性和记忆力。我们已经了解到神经元中的SOCE表现出独特的专门化， 包括快速激活和不寻常的钙依赖，其基础不容易解释 轻松地从现有的激活模型。在此应用程序中，我们的目标是构建 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SOCE中的神经递质和受体信号如何影响基本过程 突触交流、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的一系列方法 对认知、抑郁和疾病的行为分析，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钙离子进入途径的作用。 在神经系统中与从认知到疼痛的一系列功能有极大的相关性，以及 最终促进以ORAI渠道为目标的努力，用于神经系统疾病的药物发现。