Distinct role of Neurabin and Spinophilin in Synaptic Transmission and Plasticity

Neurabin 和 Spinophilin 在突触传递和可塑性中的独特作用

• 批准号: 7655181
• 负责人: HOUHUI XIA
• 金额: $ 29.96万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655181
• 关键词: AMPA Receptors; Alzheimer' s Disease; Arts; Binding; Binding Proteins; Biological; Catalysis; Cognitive; Complex; Data; Defect; Degenerative Disorder; Disease; Enzymes; F-Actin; Figs - dietary; Goals; Hippocampus (Brain); Homologous Gene; Impairment; Knowledge; Literature; Long-Term Depression; Long-Term Potentiation; Mediating; Molecular; Neurabin; Neurodegenerative Disorders; Neurons; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Population; Process; Protein phosphatase; Publishing; RNA Interference; Role; Serine; Signal Transduction; Specificity; Staging; Stimulus; Substrate Specificity; Synapses; Synaptic Transmission; Testing; Therapeutic; Vertebral column; base; calmodulin-dependent protein kinase II; density; inhibitor/antagonist; insight; novel; postsynaptic; prevent; public health relevance; response; spinophilin; synaptic depression; synaptic function; trafficking

DESCRIPTION (provided by applicant): Considerable evidence suggests that synaptic function is severely compromised in Alzheimer's disease and other neurodegenerative diseases, leading to cognitive defects even during the early stages of these diseases. It is well known that protein phosphatase-1 (PP1) plays a critical role in synaptic function. However, our preliminary data indicates that there are at least two synaptic PP1 populations which can exert differential functions on synaptic transmission. Our immediate goal is to elucidate the differential targeting and signaling mechanisms underlying these two synaptic PP1 populations. Our longer-term goal is to apply this knowledge in understanding how impairment of PP1 signaling in synaptic function can be prevented in diseases. Our newly acquired preliminary data suggest that two distinct pools of PP1, probably targeted respectively by neurabin and spinophilin, have opposite functions in synaptic transmission and play differential roles in long term depression (LTD). In this proposal, we hypothesize that neurabin and spinophilin can exert their opposite effects on basal synaptic transmission (Aim 1) through micro-targeting their cargoes (PP1) to distinct micro-compartments within synapses, acting on different substrates, i.e. Ser657 on PKC1 (and indirectly on Ser880 on GluR2) and Ser831 on GluR1, respectively. In response to LTD stimulus (Aim2), we propose to test our hypothesis that neurabin will traffic to PSD fraction to dephosphorylate GSK32, leading to synaptic depression while spinophilin does not play a role in this process. Critical domains on neurabin and spinophilin mediating their distinct effects will be elucidated in these two aims by a combination of electrophysiological recording and the state-of-the-art molecular replacement approach. In Aim3, we will hypothesize that neurabin, but not spinophilin, plays a negative role in LTP expression. We propose to determine the phosphorylation mechanism on neurabin by which LTP stimulus uses to overcome the inhibitory effects of Nrb/PP1 complex for normal LTP to occur. Finally we will also test the hypotheses that Nrb/PP1 modifies CaMKII and/or GSK32 for its inhibitory function in LTP. The results obtained from these studies will provide a better understanding of biological mechanisms that (1) regulate PP1 interaction with different binding proteins for differential substrate specificity, (2) structural basis for the critical functions of neurabin and spinophilin in synaptic functions; and (3) provide insights into therapeutic cures for the cognitive defects in patients with neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Considerable evidence suggests that synaptic function is severely compromised in Alzheimer's disease and other neurodegenerative diseases, leading to cognitive defects even during the early stages of these diseases. Our proposed study is to examine the phosphatases signaling mechanisms underlying synaptic functions. The results obtained from these studies will provide molecular insights into therapeutic cures for the cognitive defects in patients with neurodegenerative diseases.

描述（由申请人提供）：大量证据表明，阿尔茨海默病和其他神经退行性疾病中的突触功能严重受损，甚至在这些疾病的早期阶段也会导致认知缺陷。众所周知，蛋白磷酸酶-1 (PP1) 在突触功能中起着至关重要的作用。然而，我们的初步数据表明，至少有两个突触PP1群体可以对突触传递发挥不同的功能。我们的近期目标是阐明这两个突触 PP1 群体的差异靶向和信号传导机制。我们的长期目标是应用这些知识来了解如何在疾病中预防突触功能中 PP1 信号传导的损伤。我们新获得的初步数据表明，两个不同的 PP1 池可能分别是神经蛋白和亲旋蛋白的靶标，它们在突触传递中具有相反的功能，并在长期抑郁 (LTD) 中发挥不同的作用。在本提案中，我们假设神经蛋白和亲旋蛋白可以通过将其货物（PP1）微定位到突触内不同的微区室，作用于不同的底物，即分别作用于 PKC1 上的 Ser657（以及间接作用于 GluR2 上的 Ser880）和 GluR1 上的 Ser831，从而对基础突触传递（目标 1）发挥相反的作用。为了响应 LTD 刺激 (Aim2)，我们建议检验我们的假设，即神经蛋白将转运至 PSD 部分以使 GSK32 去磷酸化，导致突触抑制，而亲旋蛋白在此过程中不起作用。通过电生理记录和最先进的分子替代方法的结合，将在这两个目标中阐明神经蛋白和亲旋蛋白介导其独特作用的关键领域。在 Aim3 中，我们假设神经蛋白（而不是亲旋蛋白）在 LTP 表达中发挥负面作用。我们建议确定 LTP 刺激用于克服 Nrb/PP1 复合物对正常 LTP 发生的抑制作用的神经蛋白磷酸化机制。最后，我们还将测试 Nrb/PP1 修饰 CaMKII 和/或 GSK32 在 LTP 中的抑制功能的假设。从这些研究中获得的结果将有助于更好地理解以下生物学机制：(1) 调节 PP1 与不同结合蛋白的相互作用以实现不同的底物特异性；(2) 神经蛋白和亲旋蛋白在突触功能中的关键功能的结构基础； (3) 为神经退行性疾病患者认知缺陷的治疗提供见解。公共健康相关性：大量证据表明，阿尔茨海默病和其他神经退行性疾病中的突触功能严重受损，甚至在这些疾病的早期阶段也会导致认知缺陷。我们提出的研究是检查突触功能背后的磷酸酶信号传导机制。这些研究获得的结果将为神经退行性疾病患者认知缺陷的治疗提供分子见解。