MODULATION OF ION CHANNELS BY PHOSPHOINOSITIDE METABOLISM

通过磷酸肌醇代谢调节离子通道

• 批准号: 7956412
• 负责人: BERTIL HILLE
• 金额: $ 1.63万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956412
• 关键词: Biological Psychiatry; Cell Line; Cell membrane; Cell model; Cells; Cellular Membrane; Chemicals; Complex; Computer Retrieval of Information on Scientific Projects Database; Computer software; Confocal Microscopy; Electrophysiology (science); Enzymes; Fluorescence Resonance Energy Transfer; Funding; G Protein-Coupled Receptor Signaling; Grant; Hormonal; Institution; Ion Channel; Kinetics; Measures; Membrane Lipids; Metabolic; Metabolism; Methods; Modeling; Muscarinic M1 Receptor; Muscarinics; Pharmaceutical Preparations; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipase C; Phospholipids; Regulation; Research; Research Personnel; Resources; Signal Transduction; Source; Testing; United States National Institutes of Health; Work; base; drug of abuse; mental state; models and simulation; patch clamp; research study; virtual; voltage gated channel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究主要探讨G蛋白偶联受体（GPCR）对细胞膜脂离子通道功能的调控。它的重点是假设，许多离子通道的功能取决于一种罕见的磷脂，磷脂酰肌醇4，5-二磷酸（PIP 2）在质膜的浓度。将测量从M1毒蕈碱受体到磷脂酶C的信号步骤的动力学，以检验它们是快速的这一假设，这可能反映了预先形成的信号复合物。将测量消耗和补充PIP 2的代谢步骤的动力学，以了解PIP 2的细胞来源和动力学。所有结果将与一个全面的动力学模型拟合，以提供有关信号级联机制的更多信息。将研究PIP 2浓度变化和毒蕈碱信号传导调节KCNQ通道和电压门控Ca 2+通道（CaV通道）功能的能力。 这些方法将包括膜片钳电生理学，荧光共振能量转移，酶的动态靶向细胞膜，共聚焦显微镜和化学分析。这些实验的分析和解释将与虚拟细胞建模和仿真软件促进。大多数研究将在细胞系上进行。这项工作奠定了基础，了解荷尔蒙控制的精神状态和行动的许多药物的生物精神病学和药物滥用。