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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

基本信息

批准号：
8431374
负责人：
HOUHUI XIA
金额：
$ 29.38万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8431374
关键词：
AMPA Receptors Alzheimer&apos s Disease Binding Binding Proteins Biological Catalysis Cognitive Complex Data Defect Degenerative Disorder Disease Enzymes F-Actin 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 Synaptic plasticity Testing Therapeutic Vertebral column abstracting base calmodulin-dependent protein kinase II density inhibitor/antagonist insight novel postsynaptic prevent response spinophilin synaptic depression synaptic function trafficking

项目摘要

Abstract: 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 PKC¿ (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 GSK3¿, 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 GSK3¿ 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 neuro-degenerative diseases.

摘要：相当多的证据表明，突触功能严重受损，阿尔茨海默病和其他神经退行性疾病，导致认知缺陷即使在这些疾病的早期阶段。众所周知，蛋白质磷酸酶-1（PP 1）在突触功能中起关键作用。然而，我们的初步数据表明，至少有两个突触PP 1群体可以发挥作用，突触传递的差异功能。我们的直接目标是阐明这两种突触PP 1的差异靶向和信号传导机制人口。我们的长期目标是应用这些知识来了解在疾病中可以预防突触功能中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PP 1池，分别由neurabin和spinophilin靶向，在突触中具有相反的功能，在长期抑郁症（LTD）中发挥不同的作用。在这一提议中，我们假设neurabin和spinophilin可以对基底神经元产生相反的作用，突触传递（Aim 1）通过微靶向其货物（PP 1）到不同的突触内的微区室，作用于不同的底物，即Ser 657， PKC β（和间接作用于GluR 2上的Ser 880）和GluR 1上的Ser 831。在对LTD刺激（Aim 2）的反应，我们建议测试我们的假设，即neurabin将运输到PSD部分去磷酸化GSK 3，导致突触抑制，亲棘素在该过程中不起作用。neurabin的关键结构域，在这两个目标中，将通过以下方式阐明介导其不同作用的亲棘素：结合电生理记录和最先进的分子替代方法。在Aim 3中，我们假设neurabin，而不是spinophilin，在LTP表达中起负作用。我们建议确定磷酸化 LTP刺激用于克服抑制效应的neurabin机制 Nrb/PP 1复合物的水平对正常LTP的发生有重要作用。最后，我们还将测试假设 Nrb/PP 1修饰CaMKII和/或GSK 3 <$以抑制LTP。从这些研究中获得的结果将使人们更好地了解生物学机制：（1）调节PP 1与不同结合蛋白的相互作用，不同的底物特异性，（2）neurabin关键功能的结构基础和spinophilin在突触功能;和（3）提供洞察治疗治愈神经退行性疾病患者的认知缺陷。