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: 8033097
• 负责人: HOUHUI XIA
• 金额: $ 30.44万
• 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/8033097
• 关键词: AMPA Receptors; Alzheimer' s Disease; Binding; Binding Proteins; Biological; Catalysis; Cognitive; Complex; Data; Defect; Degenerative Disorder; Disease; Enzymes; F-Actin; Goals; Health; 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; Synaptic plasticity; Testing; Therapeutic; Vertebral column; base; calmodulin-dependent protein kinase II; density; inhibitor/antagonist; insight; novel; postsynaptic; prevent; 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，在阿尔茨海默病和其他神经退行性疾病中，突触功能严重受损，甚至在这些疾病的早期阶段导致认知缺陷。蛋白磷酸酶-1（PP 1）在突触功能中起着重要作用。然而，我们的初步数据表明，有至少两个突触PP 1人口可以发挥差异功能的突触传递。我们的近期目标是阐明这两个突触PP 1群体的差异靶向和信号传导机制。我们的长期目标是将这些知识应用于了解如何在疾病中预防突触功能中PP 1信号传导的损伤。我们新获得的初步数据表明，两个不同的池的PP 1，可能分别由neurabin和spinophilin的目标，有相反的功能，在突触传递和长期抑郁症（LTD）发挥不同的作用。在这个建议中，我们假设neurabin和spinophilin可以发挥其相反的作用，对基础的突触传递（目的1），通过微靶向其货物（PP 1）到不同的微隔室内的突触，作用于不同的底物，即Ser 657对PKC 1（和间接对Ser 880对GluR 2）和Ser 831对GluR 1，分别。在响应LTD刺激（Aim 2），我们建议测试我们的假设，即neurabin将交通PSD部分去磷酸化GSK 32，导致突触抑制，而spinophilin不发挥作用，在这个过程中。neurabin和spinophilin介导其独特的效果的关键领域将阐明在这两个目标的电生理记录和国家的最先进的分子替代方法的组合。在Aim 3中，我们假设neurabin而不是spinophilin在LTP表达中起负作用。我们建议确定神经肽的磷酸化机制，LTP刺激用于克服Nrb/PP 1复合物对正常LTP发生的抑制作用。最后，我们还将测试Nrb/PP 1修饰CaMKII和/或GSK 32在LTP中的抑制功能的假设。从这些研究中获得的结果将提供更好的理解生物学机制，（1）调节PP 1与不同结合蛋白的相互作用，以获得不同的底物特异性，（2）neurabin和spinophilin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的认知缺陷的治疗提供见解。公共卫生相关性：相当多的证据表明，在阿尔茨海默病和其他神经退行性疾病中，突触功能严重受损，甚至在这些疾病的早期阶段导致认知缺陷。我们的研究目的是探讨磷酸酶在突触功能中的信号传导机制。从这些研究中获得的结果将为神经退行性疾病患者的认知缺陷的治疗提供分子见解。