Elementary Events of Intracellular Calcium Signaling

细胞内钙信号传导的基本事件

• 批准号: 7495966
• 负责人: IAN PARKER
• 金额: $ 38.43万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495966
• 关键词: Address; Alzheimer' s Disease; Biological Models; Biophotonics; Calcium; Calcium Oscillations; Calcium Signaling; Cell Death; Cell membrane; Cell physiology; Cells; Cessation of life; Complex; Cytosol; Defect; Diffusion; Disease; Disruption; Elevation; Endoplasmic Reticulum; Event; Extracellular Fluid; Functional disorder; Generations; Goals; ITPR1 gene; Image; Image Analysis; Imagery; Imaging Techniques; Individual; Inositol; Ions; Kinetics; Lead; Life; Ligands; Localized; Location; Maps; Measures; Mediating; Membrane; Methods; Microscopy; Mitochondria; Neuroblastoma; Neurons; Neurotransmitters; Nuclear; Oocytes; Optics; Parkinson Disease; Pathogenesis; Pathway interactions; Pattern; Physiological; Plasma; Process; Property; Protein Overexpression; Range; Regulation; Resolution; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Site; Specificity; Synaptic Transmission; Techniques; Technology; Time; Total Internal Reflection Fluorescent; brain cell; cell type; computer generated; improved; inositol-1,4,5-triphosphate receptor; ligand gated channel; neuronal cell body; novel; patch clamp; photolysis; receptor; research study; response; second messenger; single molecule; spatiotemporal; tool; voltage; voltage gated channel

DESCRIPTION (provided by applicant): The entry of Ca2+ ions into the cytosol from the extracellular fluid and from endoplasmic reticulum (ER) stores is used as a signaling mechanism by virtually all cell types to regulate functions as diverse as electrical excitability, secretion, proliferation and cell death. Improved optical technology now enables visualization of a hierarchy of Ca2+ signaling events, ranging from openings of single-channel Ca2+-permeable channels ('fundamental' events), concerted openings of clustered channels ('elementary' events) and propagating Ca2+ waves. The localized free [Ca2+] elevations arising through individual and clustered channels serve autonomous signaling functions, and their activity may further be coordinated through Ca2+ diffusion and Ca2+-induced Ca2+ release to propagate global cellular Ca2+ waves: Fundamental and elementary events thus form hierarchical building blocks underlying the complex spatiotemporal Ca2+ signals hat permit graded and selective regulation of cell functions. Elucidation of their generation, interaction and functional consequences is, therefore, pivotal to understand the physiological functioning of the ubiquitous Ca2+ messenger pathway and its involvement in disease. Our overall goals are to elucidate how cells generate the hierarchy of Ca2+ signals, how these are utilized for specific and localized regulation of effector responses, and how disruptions in the signaling pathway may be involved in disease pathogenesis. By utilizing advanced biophotonic tools - including confocal, multi-focal and total internal reflection microscopy, in conjunction with photolysis of caged second messengers and neurotransmitters we aim to: (i) Develop improved optical techniques so as to image Ca2+ flux through individual channels in the plasma membrane and ER of intact cells, (ii) Utilize simultaneous imaging of hundreds of single-channels to explore differences in their gating, and study self- and inter-channel modulation by Ca2+ microdomains. (iii) Elucidate how the activity of individual IP3R at a release site is orchestrated to generate elementary Ca2+ puffs, (iv) Investigate the hierarchy of spatio-temporal patterning of the IPs/Ca2+ messenger pathway in neuronal signaling, and in the pathogenesis of Parkinson's disease. Calcium serves a 'life or death' function in virtually all cells of the body, regulating processes as diverse as the heartbeat and synaptic transmission between brain cells and is implicated in numerous diseases including Alzheimer's and Parkinson's. Our goal is to elucidate the hierarchical mechanisms by which Ca2+ signals are generated at levels from single molecules to the whole cell, with the dual aims of better understanding their normal functioning and how disruptions in Ca2+ signaling, may lead to disease.

描述（由申请人提供）：Ca 2+离子从细胞外液和内质网（ER）库进入胞质溶胶被用作几乎所有细胞类型的信号传导机制，以调节电兴奋性、分泌、增殖和细胞死亡等多种功能。改进的光学技术现在能够可视化Ca 2+信号事件的层次结构，范围从单通道Ca 2+渗透通道的开口（“基本”事件），集群通道的协调开口（“基本”事件）和传播Ca 2+波。通过个体和集群通道产生的局部游离[Ca 2 +]升高提供自主信号功能，并且它们的活性可以进一步通过Ca 2+扩散和Ca 2+诱导的Ca 2+释放来协调，以传播全局细胞Ca 2+波：因此，基本和基本事件形成了复杂时空Ca 2+信号的分层构建块，这些信号允许分级和选择性调节细胞功能。因此，阐明它们的产生、相互作用和功能后果对于理解普遍存在的Ca 2+信使途径的生理功能及其在疾病中的参与至关重要。我们的总体目标是阐明细胞如何产生Ca 2+信号的层次结构，这些是如何用于特定的和本地化的调节效应反应，以及如何在信号通路的中断可能参与疾病的发病机制。通过利用先进的生物光子工具-包括共聚焦，多焦点和全内反射显微镜，结合笼状第二信使和神经递质的光解，我们的目标是：（i）开发改进的光学技术，以便对通过完整细胞的质膜和内质网中的各个通道的Ca 2+通量进行成像，（ii）利用数百个单通道的同时成像来探索其门控的差异，并研究Ca 2+微区的自我和通道间调制。(iii)阐明如何在一个单独的IP 3R释放网站的活动是精心策划，以产生基本的Ca 2+泡芙，（iv）调查的层次结构的时空图案的IP/Ca 2+信使途径在神经元信号传导，并在帕金森氏病的发病机制。钙在身体的几乎所有细胞中都起着“生或死”的作用，调节着心跳和脑细胞之间的突触传递等多种过程，并与包括阿尔茨海默氏症和帕金森氏症在内的许多疾病有关。我们的目标是阐明Ca 2+信号在从单个分子到整个细胞的水平上产生的分层机制，其双重目标是更好地了解它们的正常功能以及Ca 2+信号传导的中断如何导致疾病。