Calcium Dynamics in Exocytosis and Synaptic Facilitation

胞吐作用和突触促进中的钙动力学

• 批准号: 0817703
• 负责人: Victor Matveev
• 金额: $ 30.56万
• 依托单位: New Jersey Institute of Technology
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0817703&HistoricalAwards=false
• 关键词: Calcium; Dynamics; Exocytosis; Synaptic; Facilitation

This project will use a combination of analytical, computational and experimental techniques to gain a deeper understanding of the synaptic release of neurotransmitter, termed exocytosis. It will address such open questions as the precise sequence of steps linking calcium ion entry into the cell to exocytosis, the involvement of individual calcium channels in neurotransmitter release, and the mechanisms of transient calcium-dependent facilitation of synaptic response, presumably caused by the accumulation of calcium at the exocytosis site. More specifically, this project will focus on the impact of intrinsic and externally applied calcium binding substances termed calcium buffers on exocytosis and its facilitation, using mathematical and computational modeling of calcium diffusion inside the cell. The importance of calcium buffers stems from the fact that they absorb more than 95% of calcium ions entering the cell; further, the sensitivity of exocytosis and facilitation to applied buffers provides one of the most widely used methods to probe the intrinsic calcium sensitivity of these processes. The first specific goal of this project is to reveal the effect of such buffers on the cooperativity of individual calcium channels in triggering exocytosis of a single vesicle, and to re-examine the so-called calcium current cooperativity measurements that probe the arrangement of channels at the release site. The second specific goal is to examine the proposed non-local property of the buffer saturation phenomenon, whereby the transient whole-terminal depletion of free buffer by calcium influx through one group of channels may cause subsequent opening of the same or another group of channels to produce a greater calcium elevation. Further, the competition between two calcium buffers in their regulation of intracellular calcium will be explored. Finally, this project will examine the possible functional consequences of synaptic facilitation for the dynamics of neural circuits.Neurotransmitter release at chemical synapses (exocytosis) represents the most common form of communication between two neurons in any biological neural system, including the mammalian cortex, and the knowledge of its mechanisms is indispensable for a full understanding of inter-neuronal interactions and neural information processing. Further, the regulation of neurotransmitter release and binding to receptors represents the main pharmacological treatment method in many neurological and psychiatric pathologies. The importance of this project stems from its combined use of advanced computational tools and experimental physiological techniques in gaining deeper understanding of the neurotransmitter release process, known to depend on the action of calcium ions inside the cell. This project will focus on the precise sequence of exocytosis steps starting with the entry of calcium through cell membrane calcium channels, their subsequent accumulation and binding to intracellular calcium-binding substances, and ending with the calcium-triggered release of neurotransmitter-filled vesicles into the synapse. This investigation should also lead to a better understanding of other vital physiological processes controlled by calcium ions, from gene expression regulation to muscle cell contraction in the heart. Further, this project will involve the use and further development of a publicly accessible computational modeling tool called CalC ("Calcium Calculator"), designed by the Principle Investigator for the modeling of three-dimensional calcium ion diffusion inside the cell (http://www.calciumcalculator.org). This will contribute to the infrastructure for computational modeling in the biological sciences and will also serve as a useful training instrument in the fields of cell neurophysiology and biophysics. All modeling results obtained in the course of this project will be made publicly available through the on-line model database, ensuring the most rapid and effective dissemination of the obtained results. Finally, this project will create student training opportunities in the highly interdisciplinary fields of mathematical biology, biophysics and computational neuroscience, including the training of students from under-represented ethnic groups, since this work will be conducted in an institution with one of the most ethnically diverse student bodies in the country (NJIT).

该项目将结合分析，计算和实验技术，以更深入地了解神经递质的突触释放，称为胞吐作用。 它将解决诸如将钙离子进入细胞的精确序列与胞吐作用的确切序列，单个钙通道在神经递质释放中的参与以及瞬时钙依赖性突触反应的促进的机制，这可能是由脑在胞吞作用部位积聚引起的。 更具体地说，该项目将使用称为钙缓冲液对胞外生命的固有和外部施用的钙结合物质的影响，并使用细胞内钙扩散的数学和计算建模。 钙缓冲液的重要性源于它们吸收超过95％进入细胞的钙离子的事实。此外，胞吐作用和促进对应用缓冲液的敏感性提供了探测这些过程内在钙灵敏度的最广泛使用的方法之一。 该项目的第一个具体目标是揭示此类缓冲液对单个钙通道在触发单个囊泡的胞吐作用方面的协同性的影响，并重新检查所谓的钙电流合作测量，以探测释放位点的通道布置。 第二个具体目标是检查缓冲饱和现象的拟议的非本地特性，从而通过一组通道通过钙涌入钙的瞬时游离缓冲液的瞬时全末端耗竭可能会导致随后开放相同或另一组通道以产生更大的钙升高。 此外，将探索两个钙缓冲液之间的竞争，以调节细胞内钙的调节。 最后，该项目将检查突触促进对神经回路动力学的可能功能后果。化学突触中的神经递质释放（胞吐作用）代表了任何生物神经系统中两个神经元之间两种通信的最常见形式形式，包括哺乳动物皮质的机制以及其机制的知识，是对其进行不完整的相互作用的知识。 此外，神经递质释放并与受体结合的调节代表了许多神经和精神病病理学中的主要药理治疗方法。该项目的重要性源于其对先进计算工具和实验生理技术的联合使用，在对神经递质释放过程中的更深入了解中，已知取决于细胞内钙离子的作用。 该项目将重点关注钙的精确顺序，从钙从细胞膜钙通道进入，随后的积累并与细胞内钙结合物质结合开始，并以钙触发的神经递质填充囊泡释放到突触中。 这项研究还应使人们更好地理解钙离子控制的其他重要生理过程，从基因表达调节到心脏的肌肉细胞收缩。 此外，该项目将涉及由主要研究者设计和进一步开发称为CALC（“钙计算器”）的公共访问的计算建模工具，该工具是由主要研究者设计的，用于对单元内三维钙离子扩散的建模（http://wwww.calciumcalculator.org）。 这将有助于生物科学中计算建模的基础设施，并将在细胞神经生理学和生物物理学领域充当有用的训练工具。在本项目过程中获得的所有建模结果将通过在线模型数据库公开可用，以确保对获得的结果最快，最有效的传播。 最后，该项目将在数学生物学，生物物理学和计算神经科学的高度跨学科领域创造学生培训机会，包括对代表性不足的种族群体的学生培训，因为这项工作将与该机构一起在该机构中进行，是该国最多样化的学生尸体之一（NJIT）。