Pin1 in Synaptic Plasticity and Translation

突触可塑性和翻译中的 Pin1

• 批准号: 7860521
• 负责人: James S Malter
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860521
• 关键词: Ablation; Alzheimer' s Disease; Anisomycin; Apoptotic; Behavioral; Binding; Binding Proteins; Biochemical; Brain; C-terminal; Catabolism; Cell Nucleus; Cells; Chemicals; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Data; Dendrites; Dendritic Spines; Development; Enzymes; Genetic; Genetic Transcription; Glutamate Receptor; Glutamates; Hippocampus (Brain); Human; Learning; Location; Long-Term Potentiation; Maintenance; Mediating; Memory; Messenger RNA; Microtubule-Associated Proteins; Mitotic; Modification; Molecular; Mus; N-terminal; Neurons; Peptides; Peptidylprolyl Isomerase; Phosphorylation; Phosphotransferases; Play; Preparation; Process; Protein Biosynthesis; Protein Dephosphorylation; Protein Synthesis Induction; Proteins; Regulation; Role; Signal Transduction; Site; Slice; Specificity; Synapses; Synaptic plasticity; Translations; Western Blotting; age related neurodegeneration; chemical genetics; human FRAP1 protein; information processing; inhibitor/antagonist; neuronal cell body; protein function; protein kinase C zeta; seryl-proline; transcription factor; Ablation; Alzheimer' s Disease; Anisomycin; Apoptotic; Behavioral; Binding; Binding Proteins; Biochemical; Brain; C-terminal; Catabolism; Cell Nucleus; Cells; Chemicals; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Data; Dendrites; Dendritic Spines; Development; Enzymes; Genetic; Genetic Transcription; Glutamate Receptor; Glutamates; Hippocampus (Brain); Human; Learning; Location; Long-Term Potentiation; Maintenance; Mediating; Memory; Messenger RNA; Microtubule-Associated Proteins; Mitotic; Modification; Molecular; Mus; N-terminal; Neurons; Peptides; Peptidylprolyl Isomerase; Phosphorylation; Phosphotransferases; Play; Preparation; Process; Protein Biosynthesis; Protein Dephosphorylation; Protein Synthesis Induction; Proteins; Regulation; Role; Signal Transduction; Site; Slice; Specificity; Synapses; Synaptic plasticity; Translations; Western Blotting; age related neurodegeneration; chemical genetics; human FRAP1 protein; information processing; inhibitor/antagonist; neuronal cell body; protein function; protein kinase C zeta; seryl-proline; transcription factor

Consolidation of synaptic plasticity and memory requires biochemical alterations in the molecular composition of the synapse. The process of consolidation involves multiple processes including local translation of preexisting, dendritic mRNAs and results in changes in synaptic efficacy and storage of new memories that persist from days to years. While a few of the effectors of memory have been identified, relatively little is understood about how these molecules govern the induction of long-term forms of synaptic plasticity. We now show that Pin1, a cis-trans peptidyl-prolyl isomerase with specificity for Ser-Pro or Thr-Pro peptide bonds, plays a key role in synaptic plasticity. Pin1 is present in dendrites and spines and under basal conditions, suppresses dendritic protein synthesis. Glutamate signaling inactivates Pin1, leading to increased translation of many proteins including the plasticity related kinases PKMand PKC In the genetic absence of Pin1, hippocampal L-LTP is increased as are the levels of PKMand PKC. PKMand PKCactivity were necessary to maintain the suppression of Pin1 activity after glutamate signaling as well as dendritic translation. These data suggest glutamatergic signaling inhibits Pin1 which leads to the translation of PKM and PKC. Once produced, these kinases then support on-going dendritic translation partially by suppressing Pin1. As such our aims are to determine 1) the role of PKMin regulating Pin1 and 2) further characterize PKM function by identifying its downstream targets through chemical-genetics.

突触可塑性和记忆的合并需要突触的分子组成的生化改变。整合过程涉及多个过程，包括先前存在的局部翻译，树突状mRNA，并导致突触效率的变化和新记忆的储存变化，这些记忆持续到几天到几年。尽管已经确定了一些记忆的影响，但对于这些分子如何控制长期诱导的诱导方式，相对较少了解，我们现在表明，在Ser-Pro或Thr-Pro Peel键特异性的Cis-Trans Petidyl----------- pen1在突触可塑性中起关键作用。 PIN1存在于树突和棘中，在基本条件下，抑制了树突蛋白的合成。谷氨酸信号传导使PIN1失活，从而导致许多蛋白质的翻译增加，包括相关的激酶PKM和PKC在遗传不存在PIN1的情况下，海马L-LTP也增加了PKM和PKC的水平。在谷氨酸信号传导以及树突流翻译后维持PIN1活性的抑制是必要的。这些数据表明谷氨酸能信号传导抑制PIN1，从而导致PKM和PKC的翻译。一旦产生，这些激酶就会通过抑制PIN1来部分支持持续的树突流。因此，我们的目的是确定1）PKM在调节PIN1和2）通过化学基因识别其下游靶标在调节PIN1和2）的作用。