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.

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