Roles and regulation of PI(3,5)P2 and PI5P in neurons

PI(3,5)P2和PI5P在神经元中的作用和调节

• 批准号: 9052226
• 负责人: Lois S Weisman
• 金额: $ 43.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052226
• 关键词: AMPA Receptors; Affect; Bicuculline; Calcium; Calcium ion; Chemicals; Chronic; Collaborations; Complex; Data; Dendritic Spines; Down-Regulation; Excitatory Synapse; Fluorescent Probes; Goals; Health; Hippocampus (Brain); Human; Knowledge; Learning; Lipids; Long-Term Depression; Memory; Michigan; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; N-Methylaspartate; Nervous system structure; Neurons; PI3 gene; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Play; Proteins; Regulation; Role; Signal Pathway; Slice; Synapses; Synaptic plasticity; Tamoxifen; Testing; Universities; Up-Regulation; base; cell type; inhibitor/antagonist; inorganic phosphate; insight; mutant; neuropsychiatric disorder; postsynaptic; presynaptic; receptor; trafficking

DESCRIPTION (provided by applicant): Our long-range goals are to determine the roles and regulation of phosphatidylinositol (3, 5)-bis phosphate (PI3,5P2) in neurons. We recently made the unexpected discovery that PI3, 5P2 is a critical upstream regulator of synaptic strength. PI3,5P2 is in very low abundance. Its synthesis requires the lipid kinase PIKfyve and PIKfyve regulators: Vac14 and Fig4. Our studies of mouse mutants, as well as discovery of human patients with mutations in Fig4, establish the general importance of PI3, 5P2 within the nervous system. We recently made two findings that change current knowledge of the roles of the PI3, 5P2 signaling pathway in neurons. First, the Vac14-PIKfyve-Fig4 complex plays an inhibitory role at excitatory synapses, and affects both presynaptic and postsynaptic function. Second, studies shown here strongly suggest that the Vac14-PIKfyve-Fig4 complex, via its role in endomembrane trafficking, plays a critical role in specific forms of synaptic plasticity. In additin, emerging data from us and others indicate that PI3, 5P2 is a critical upstream regulator of multiple pathways both in neurons and other cell- types. Here we focus on the requirement of PIKfyve, Vac14 and Fig4 for chemical long-term depression and homeostatic down scaling. In addition, in collaboration with Dr. Haoxing Xu (U. Michigan) we have developed a fluorescent probe for PI3,5P2. We anticipate that this probe will greatly expand the ability of us and others to study PI3,5P2 in neurons. The overall goals of this proposal are to 1) Determine whether PI3, 5P2 and PI5P are essential for specific forms of synaptic plasticity. 2) Determine whether calcium is required for the transient activation of PIKfyve, and whether PIKfyve and/or AMPA receptor localization changes during this activation. These proposed studies have the potential to provide significant advances in current knowledge of the molecular basis of synaptic plasticity, as well as advance understanding of molecular mechanisms required for learning and memory.

描述（由申请人提供）：我们的远程目标是确定神经元中磷脂酰肌醇（3，5）-Bis磷酸（PI3,5P2）的作用和调节。我们最近意外发现，PI3，5P2是突触强度的关键上游调节器。 PI3,5P2的丰度非常低。它的合成需要脂质激酶Pikfyve和Pikfyve调节剂：VAC14和FIG4。我们对小鼠突变体的研究以及在图4中发现了突变患者的研究，确定了神经系统中PI3，5p2的一般重要性。最近，我们提出了两个发现，这些发现改变了当前对神经元中PI3，5p2信号通路的作用的知识。首先，Vac14-Pikfyve-Fig4复合物在兴奋性突触中起抑制作用，并影响突触前和突触后功能。其次，这里的研究强烈表明，VAC14-Pikfyve-Fig4复合物通过其在内膜运输中的作用，在特定形式的突触可塑性中起着至关重要的作用。在附加素中，来自美国和其他的新兴数据表明，PI3，5P2是神经元和其他细胞类型中多个途径的关键上游调节剂。在这里，我们着重于Pikfyve，Vac14和Fig4对化学长期抑郁症和稳态下缩放的需求。此外，与Haoxing Xu（美国密歇根州）合作，我们开发了PI3,5P2的荧光探针。我们预计该探测器将大大扩展我们和其他人在神经元中研究PI3,5P2的能力。该提案的总体目标是1）确定PI3，5P2和PI5P是否对于特定形式的突触可塑性至关重要。 2）确定Pikfyve的瞬时激活是否需要钙，以及在此激活过程中Pikfyve和/或AMPA受体定位是否会发生变化。这些提出的研究有可能在当前有关突触可塑性的分子基础的知识以及对学习和记忆所需的分子机制的进步中提供重大进展。