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: 8853956
• 负责人: Lois S Weisman
• 金额: $ 43.84万
• 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/8853956
• 关键词: AMPA Receptors; Affect; Bicuculline; Calcium; Calcium ion; Chemicals; Chronic; Collaborations; Complex; Data; Dendritic Spines; Disease; Down-Regulation; Excitatory Synapse; Fluorescent Probes; Goals; Hippocampus (Brain); Human; Knowledge; Learning; Lipids; Long-Term Depression; Memory; Michigan; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; N-Methylaspartate; Nervous system structure; Neurons; 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; neuropsychiatry; postsynaptic; presynaptic; public health relevance; 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）：我们的长期目标是确定磷脂酰肌醇 (3, 5)-二磷酸 (PI3,5P2) 在神经元中的作用和调节。我们最近意外发现PI3、5P2是突触强度的关键上游调节因子。 PI3,5P2 的丰度非常低。其合成需要脂质激酶 PIKfyve 和 PIKfyve 调节剂：Vac14 和 Fig4。我们对小鼠突变体的研究以及 Fig4 中携带突变的人类患者的发现，确立了 PI3、5P2 在神经系统中的普遍重要性。我们最近的两项发现改变了目前对 PI3、5P2 信号通路在神经元中作用的认识。首先，Vac14-PIKfyve-Fig4 复合物对兴奋性突触起抑制作用，并影响突触前和突触后功能。其次，这里显示的研究强烈表明，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发挥着关键作用。此外，我们和其他人的新数据表明，PI3、5P2 是神经元和其他细胞类型中多种途径的关键上游调节因子。在这里，我们重点关注 PIKfyve、Vac14 和 Fig4 对化学长期抑制和稳态缩小的要求。此外，我们与徐浩兴博士（美国密歇根州）合作开发了PI3,5P2的荧光探针。我们预计该探针将极大地扩展我们和其他人研究神经元中 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 瞬时激活是否需要钙，以及在此激活过程中 PIKfyve 和/或 AMPA 受体定位是否发生变化。这些拟议的研究有可能为当前突触可塑性分子基础的知识提供重大进展，并促进对学习和记忆所需分子机制的理解。