Store-operated channels in the nervous system

神经系统中的存储操纵通道

• 批准号: 7356042
• 负责人: Murali Prakriya
• 金额: $ 33.03万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-13 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7356042
• 关键词: Address; Alzheimer' s Disease; Axon; Biological Assay; Brain; Caenorhabditis elegans; Candidate Disease Gene; Cell Survival; Cell membrane; Cell physiology; Cells; Characteristics; Chromosome Pairing; Cytosol; Dependence; Disease; Electrophysiology (science); Endoplasmic Reticulum; Etiology; Event; Family; Fingerprint; Foundations; Future; Gene Expression; Genetic Transcription; Goals; Hematopoietic; Homeostasis; Human; Immunologic Deficiency Syndromes; Ion Channel; Ions; Kinetics; Laboratories; Link; Luciferases; Mammals; Measures; Mediating; Membrane; Methods; Microscopy; Molecular; Monitor; NF-AT; Nature; Nervous system structure; Neurons; Nuclear Translocation; Organelles; Pathway interactions; Patients; Pharmacology; Physiological; Prevention strategy; Process; Property; Pump; Range; Regulation; Reporter; Research Personnel; Role; Signal Transduction; Source; Specificity; Stimulus; Synapses; Synaptic plasticity; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Work; base; calcium indicator; cell type; human STIM1 protein; improved; insight; mast cell; neuronal survival; neurotransmitter release; neurotrophic factor; novel; nuclear factors of activated T-cells; patch clamp; programs; response; sensor; tool; transcription factor

Ca2+ signals in the nervous system mediate a remarkable variety of cellular functions, including neurotransmitter release, membrane excitability, and proliferation. To control the dynamic features of the signals mediated by this multifunctional messenger and generate specificity, neurons are endowed with a large repertoire of ion channels, pumps, and cellular organelles that work together to sculpt Ca2+ signals. In this repertoire, one of the least understood is the store-operated channel (SOC). SOCs, defined as channels in the plasma membrane that open in response to depletion of Ca2+ from the endoplasmic reticulum (ER), are a widespread mechanism for triggering Ca2+ influx into the cell. In the nervous system, SOCs are known to influence neurotransmitter release and synaptic plasticity, and aberrant signaling involving SOCs is associated with Alzheimer's disease. However, very little is known about the basic properties of neuronal SOCs and the mechanisms linking store depletion to channel activation. The long-term goals of this work are to understand the biophysical characteristics, molecular basis, and functional organization of neuronal SOCs, to identify stimuli that trigger their activation, and to elucidate the downstream consequences of their activation for neuronal function. Recent advances in fluorescent calcium indicators and microscopy provide an opportunity to gain insight into the nature of the SOC activation process. The overall thrust of present proposal is to exploit new tools to probe the store-operated Ca2+ signaling network in neurons, which is comprised of SOCs and the ER, and to explore downstream consequences of this signaling for gene expression. Our immediate objectives are: (1) Define the biophysical properties of neuronal SOCs using patch-clamp electrophysiology. (2) Define the ER Ca2+-dependence of SOC activation by employing cameleon to measure ER Ca2+ signals. How does this compare to the ER Ca2+-dependence of the activation of STIM1, a candidate molecule for the Ca2+ sensor that communicates information about [Ca2+]ER to SOCs? (3) Investigate the role of SOCs in initiating Ca2+-dependent gene expression mediated by the transcription factor, NFAT. Recent work indicates that NFAT is involved in several essential functions such as axonal outgrowth, neuronal survival, and synapse plasticity. An improved understanding of the biophysical properties, activation mechanisms, and functions of SOCs in the nervous system could ultimately reveal novel check points for the regulation of neuronal function by Ca2+, leading to new strategies for the prevention and treatment of diseases such as Alzheimer's disease.

神经系统中的Ca~(2+)信号调节多种细胞功能，包括 神经递质释放、膜兴奋性和增殖。控制的动态特征 由这种多功能信使介导的信号并产生特异性，神经元被赋予了 大量的离子通道、泵和细胞器共同作用来塑造钙信号。在……里面 这个曲目，人们最不了解的一个是商店经营的渠道(SOC)。SoC，定义为通道 在内质网(ER)中因钙离子耗竭而开放的质膜中， 是一种广泛存在的触发钙离子流入细胞的机制。在神经系统中，SOC是已知的 影响神经递质释放和突触可塑性，以及涉及SOC的异常信号 与阿尔茨海默氏症有关。然而，人们对神经元的基本特性知之甚少。 SoC和将存储耗尽与通道激活联系起来的机制。这项工作的长期目标是 了解神经元的生物物理特征、分子基础和功能组织 以确定触发其激活的刺激，并阐明其下游后果 激活神经功能。荧光钙指示剂和显微镜的最新进展提供了 有机会深入了解SOC激活过程的性质。目前的总体主旨是 建议开发新的工具来探测神经元中存储操作的钙信号网络，这是 由SOC和ER组成，并探索该信号对基因的下游影响 表情。我们的近期目标是：(1)定义神经元SOC的生物物理特性 膜片钳电生理学。(2)定义SOC激活的内质网钙依赖关系 Cameleon测量内质网钙信号。这与内质网钙离子依赖的激活相比如何 STIM1，一个钙离子传感器的候选分子，向SOC传递关于[钙]ER的信息？ (3)研究SOCs在转录介导的钙依赖基因表达中的作用 因数，NFAT。最近的研究表明，NFAT参与了几种基本功能，如轴突 突触生长、神经元存活和突触可塑性。加深了对生物物理学的理解 神经系统中SOC的属性、激活机制和功能最终可能揭示 钙离子调节神经元功能的新检查点，导致了新的策略 防治阿尔茨海默病等疾病。