MODULATION OF ION CHANNELS BY PHOSPHOINOSITIDE METABOLISM

通过磷酸肌醇代谢调节离子通道

• 批准号: 8362510
• 负责人: BERTIL HILLE
• 金额: $ 1.05万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362510
• 关键词: Biological Psychiatry; Cell Line; Cell membrane; Cell model; Cells; Cellular Membrane; Chemicals; Complex; Confocal Microscopy; Electrophysiology (science); Enzymes; Fluorescence Resonance Energy Transfer; Funding; G Protein-Coupled Receptor Signaling; Grant; Hormonal; Ion Channel; Kinetics; Measures; Membrane Lipids; Metabolic; Metabolism; Methods; Modeling; Muscarinic M1 Receptor; Muscarinics; National Center for Research Resources; Pharmaceutical Preparations; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipase C; Phospholipids; Principal Investigator; Regulation; Research; Research Infrastructure; Resources; Signal Transduction; Source; Testing; United States National Institutes of Health; Work; base; cost; drug of abuse; mental state; models and simulation; patch clamp; research study; simulation software; virtual; voltage gated channel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project concerns the regulation of ion-channel function by G-protein-coupled receptor (GPCR) signaling to membrane lipids. It focuses on the hypothesis that the function of many ion channels depends on the concentration of one rare phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2) in the plasma membrane. The kinetics of signaling steps from M1 muscarinic receptors to phospholipase C will be measured to test the hypothesis that they are fast, perhaps reflecting a preformed signaling complex. The kinetics of the metabolic steps that deplete and replenish PIP2 will be measured to understand the cellular sources and dynamics of PIP2. All results will be fitted with a comprehensive kinetic model to provide additional information on the mechanisms of the signaling cascade. The ability of PIP2 concentration changes and muscarinic signaling to modulate function of KCNQ channels and voltage-gated Ca2+ channels (CaV channels) will be studied. The methods will include patch-clamp electrophysiology, fluorescence resonance energy transfer, dynamic targeting of enzymes to cellular membranes, confocal microscopy, and chemical analysis. Analysis and interpretation of these experiments will be facilitated with the Virtual Cell modeling and simulation software. Most of the studies will be done on cell lines. This work lays the basis for understanding hormonal control of mental state and the actions of many drugs of biological psychiatry and of drugs of abuse.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 该项目涉及通过G蛋白偶联受体（GPCR）信号传导对膜脂质的离子通道功能的调节。它的重点是，许多离子通道的功能取决于质膜中一种罕见的磷脂，磷脂酰肌醇4,5-双磷酸（PIP2）的浓度。将测量从M1毒蕈碱受体到磷脂酶C的信号传导步骤的动力学，以检验它们快速的假设，也许反映了预先形成的信号传导复合物。将测量耗尽和补充PIP2的代谢步骤的动力学，以了解PIP2的细胞源和动力学。所有结果都将配备一个全面的动力学模型，以提供有关信号级联机制的其他信息。 PIP2浓度变化和毒蕈碱信号传导的能力将研究KCNQ通道的功能和电压门控Ca2+通道（CAV通道）。 该方法将包括斑板钳电生理学，荧光共振能量转移，酶向细胞膜的动态靶向，共聚焦显微镜和化学分析。这些实验的分析和解释将通过虚拟细胞建模和仿真软件来促进。大多数研究将在细胞系上进行。这项工作为理解精神状态的荷尔蒙控制以及许多生物精神病学药物和虐待药物的作用的基础。