Tao Yuan-Xiang, Rumbaugh Gavin, Wang Guo-Du, Petralia Ronald S, Zhao Chengshui, Kauer Frederick W, Tao Feng, Zhuo Min, Wenthold Robert J, Raja Srinivasa N, Huganir Richard L, Bredt David S, Johns Roger A
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
J Neurosci. 2003 Jul 30;23(17):6703-12. doi: 10.1523/JNEUROSCI.23-17-06703.2003.
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.
突触N-甲基-D-天冬氨酸受体（NMDAR）表达的改变会影响NMDAR介导的突触功能及相关的持续性疼痛。NMDAR直接与一类膜相关鸟苷酸激酶（MAGUKs）结合，这类激酶在中枢神经系统中调节NMDAR在细胞表面和突触处的转运。我们在此报告，突触后致密蛋白93（PSD-93），一种突触后神经元MAGUK，在脊髓背角和前脑大量表达，在这些部位它与NMDAR亚基NR2A和NR2B共定位并相互作用。PSD-93基因的靶向破坏不仅降低了细胞表面NR2A和NR2B的表达，还降低了NMDAR介导的兴奋性突触后电流和电位，而不影响上述区域中细胞表面AMPA受体的表达或其突触功能。此外，缺乏PSD-93的小鼠对外周神经损伤或注射弗氏完全佐剂诱导的NMDAR依赖性持续性疼痛反应减弱，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的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点。
