Morphine administration alters the profile of hippocampal postsynaptic density-associated proteins -: A proteomics study focusing on endocytic proteins
Morphine administration alters the profile of hippocampal postsynaptic density-associated proteins -: A proteomics study focusing on endocytic proteins
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DOI：
10.1074/mcp.m600184-mcp200
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发表时间：
2007-01-01
影响因子：
7
通讯作者：
Devi, Lakshmi A.
中科院分区：
文献类型：
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作者：
Moron, Jose A.;Abul-Husn, Noura S.;Devi, Lakshmi A.
大量研究表明，滥用药物会导致大脑中蛋白质表达的变化，这被认为在突触可塑性中发挥了作用。药物诱导的可塑性可以通过突触的变化来调节，更具体地说，在接收和传递突触信息的突触后密度(PSD)。到目前为止，研究突触蛋白质谱的大多数研究都集中在识别突触蛋白质组上。只有少数几项研究研究了药物给药对突触形态的影响。我们应用可切割ICAT试剂的定量蛋白质组学分析技术，定量测定了吗啡给药后海马PSD蛋白水平的相对变化。我们在小鼠海马PSD中共鉴定出102个蛋白质。其中大部分是信号、运输和细胞骨架蛋白，涉及突触可塑性、学习和记忆。在被发现被吗啡注射后水平发生改变的蛋白质中，笼状蛋白的水平升高幅度最大。免疫印迹和电子显微镜研究表明，这种增加局限于PSD。吗啡处理还导致内吞机械的另外两个成分Dynamin和AP-2局部增加，这表明内吞机械关键参与了吗啡的调节作用。因为alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸(AMPA)受体被认为经历了笼蛋白介导的内吞作用，所以我们研究了吗啡对AMPA受体亚单位GluR1与笼蛋白的联系的影响。我们发现，与笼状蛋白相关的GluR1水平显著下降。综上所述，这些结果表明，通过引起突触内细胞蛋白的重新分布，吗啡调节了海马谷氨酸能突触的突触可塑性。
Numerous studies have shown that drugs of abuse induce changes in protein expression in the brain that are thought to play a role in synaptic plasticity. Drug-induced plasticity can be mediated by changes at the synapse and more specifically at the postsynaptic density (PSD), which receives and transduces synaptic information. To date, the majority of studies examining synaptic protein profiles have focused on identifying the synaptic proteome. Only a handful of studies have examined the changes in synaptic profile by drug administration. We applied a quantitative proteomics analysis technique with the cleavable ICAT reagent to quantitate relative changes in protein levels of the hippocampal PSD in response to morphine administration. We identified a total of 102 proteins in the mouse hippocampal PSD. The majority of these were signaling, trafficking, and cytoskeletal proteins involved in synaptic plasticity, learning, and memory. Among the proteins whose levels were found to be altered by morphine administration, clathrin levels were increased to the largest extent. Immunoblotting and electron microscopy studies showed that this increase was localized to the PSD. Morphine treatment was also found to lead to a local increase in two other components of the endocytic machinery, dynamin and AP-2, suggesting a critical involvement of the endocytic machinery in the modulatory effects of morphine. Because alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ( AMPA) receptors are thought to undergo clathrin-mediated endocytosis, we examined the effect of morphine administration on the association of the AMPA receptor subunit, GluR1, with clathrin. We found a substantial decrease in the levels of GluR1 associated with clathrin. Taken together, these results suggest that, by causing a redistribution of endocytic proteins at the synapse, morphine modulates synaptic plasticity at hippocampal glutamatergic synapses.