Impaired NMDA Receptor-Mediated Postsynaptic Function and Blunted NMDA Receptor-Dependent Persistent Pain in Mice Lacking Postsynaptic Density-93 Protein
Impaired NMDA Receptor-Mediated Postsynaptic Function and Blunted NMDA Receptor-Dependent Persistent Pain in Mice Lacking Postsynaptic Density-93 Protein
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DOI：
10.1523/jneurosci.23-17-06703.2003
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发表时间：
2003-07
期刊：
影响因子：
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通讯作者：
Y. Tao;Gavin Rumbaugh;Guodu Wang;R. Petralia;Chengshui Zhao;F. Kauer;F. Tao;M. Zhuo;R. Wenthold-R.-Went
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文献类型：
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作者：
Y. Tao;Gavin Rumbaugh;Guodu Wang;R. Petralia;Chengshui Zhao;F. Kauer;F. Tao;M. Zhuo;R. Wenthold-R.-Went
突触NMDA受体（NMDAR）表达的改变影响NMDAR介导的突触功能和相关的持续性疼痛。NMDAR直接与调节CNS中表面和突触NMDAR运输的膜相关鸟苷酸激酶（MAGUK）家族结合。我们在这里报告，突触后密度-93蛋白（PSD-93），突触后神经元MAGUK，在脊髓背角和前脑，在那里它共定位和相互作用与NMDAR亚基NR 2A和NR 2B大量表达。PSD-93基因的靶向破坏不仅降低表面NR 2A和NR 2B表达，而且降低NMDAR介导的兴奋性突触后电流和电位，而不影响上述区域中的表面AMPA受体表达或其突触功能。此外，缺乏PSD-93的小鼠表现出由外周神经损伤或注射完全弗氏佐剂诱导的钝化的NMDAR依赖性持续性疼痛，尽管它们对急性疼痛表现出完整的伤害性反应。PSD-93似乎对NMDAR突触靶向和功能很重要，并且是治疗持续性疼痛的潜在生化靶标。
Modification of synaptic NMDA receptor (NMDAR) expression influences NMDAR-mediated synaptic function and associated persistent pain. NMDARs directly bind to a family of membrane-associated guanylate kinases (MAGUKs) that regulate surface and synaptic NMDAR trafficking in the CNS. We report here that postsynaptic density-93 protein (PSD-93), a postsynaptic neuronal MAGUK, is expressed abundantly in spinal dorsal horn and forebrain, where it colocalizes and interacts with NMDAR subunits NR2A and NR2B. Targeted disruption of the PSD-93 gene reduces not only surface NR2A and NR2B expression but also NMDAR-mediated excitatory postsynaptic currents and potentials, without affecting surface AMPA receptor expression or its synaptic function, in the regions mentioned above. Furthermore, mice lacking PSD-93 exhibit blunted NMDAR-dependent persistent pain induced by peripheral nerve injury or injection of Complete Freund's Adjuvant, although they display intact nociceptive responsiveness to acute pain. PSD-93 appears to be important for NMDAR synaptic targeting and function and to be a potential biochemical target for the treatment of persistent pain.