Involvement of Brain-Enriched Guanylate Kinase-Associated Protein (BEGAIN) in Chronic Pain after Peripheral Nerve Injury.
Involvement of Brain-Enriched Guanylate Kinase-Associated Protein (BEGAIN) in Chronic Pain after Peripheral Nerve Injury.
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DOI：
10.1523/eneuro.0110-16.2016
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发表时间：
2016-09
期刊：
影响因子：
3.4
通讯作者：
Ito S
中科院分区：
文献类型：
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作者：
Katano T;Fukuda M;Furue H;Yamazaki M;Abe M;Watanabe M;Nishida K;Yao I;Yamada A;Hata Y;Okumura N;Nakazawa T;Yamamoto T;Sakimura K;Takao T;Ito S
周围神经损伤引起的神经性疼痛的维持主要依赖于GluN2B的磷酸化，GluN2B是n -甲基-d-天冬氨酸（NMDA）受体的亚基，位于Tyr1472 （Y1472）和随后形成的脊髓浅表背角神经元突触后密度（PSD）复合物。在这里，我们利用基于等压稳定同位素标签（iTRAQ）的比较蛋白质组学分析，在野生型和敲入型GluN2B （Y1472F-KI）的Phe突变小鼠（Y1472F-KI）中寻找脊髓背角中介导Y1472 GluN2B磷酸化下游信号传导的PSD蛋白。在几种候选蛋白中，我们重点关注了脑富集鸟苷酸激酶相关蛋白（BEGAIN），该蛋白在野生型小鼠神经损伤（SNI）后特异性上调。免疫组化分析表明，BEGAIN高度定位于脊髓背角内II层突触，SNI处理后，野生型小鼠的表达上调，而Y1472F-KI小鼠的表达上调。此外，BEGAIN缺失可以改变脊髓II层α-氨基-3-羟基-5-甲基-4-异氧唑丙酸（AMPA）受体的突触后兴奋性电流，而NMDA受体的突触后兴奋性电流却没有改变。我们证明，SNI模型中由无害刺激引起的异常疼痛在begain缺陷小鼠中显着减弱。然而，在机械刺激的生理阈值方面，幼稚野生型和begin -基因敲除小鼠没有显著差异。这些结果表明，BEGAIN通过脊髓II内层Y1472处GluN2B磷酸化激活NMDA受体，参与病理性疼痛传递。
Maintenance of neuropathic pain caused by peripheral nerve injury crucially depends on the phosphorylation of GluN2B, a subunit of the N-methyl-d-aspartate (NMDA) receptor, at Tyr1472 (Y1472) and subsequent formation of a postsynaptic density (PSD) complex of superficial spinal dorsal horn neurons. Here we took advantage of comparative proteomic analysis based on isobaric stable isotope tags (iTRAQ) between wild-type and knock-in mice with a mutation of Y1472 to Phe of GluN2B (Y1472F-KI) to search for PSD proteins in the spinal dorsal horn that mediate the signaling downstream of phosphorylated Y1472 GluN2B. Among several candidate proteins, we focused on brain-enriched guanylate kinase-associated protein (BEGAIN), which was specifically up-regulated in wild-type mice after spared nerve injury (SNI). Immunohistochemical analysis using the generated antibody demonstrated that BEGAIN was highly localized at the synapse of inner lamina II in the spinal dorsal horn and that its expression was up-regulated after SNI in wild-type, but not in Y1472F-KI, mice. In addition, alteration of the kinetics of evoked excitatory postsynaptic currents for NMDA but not those for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in spinal lamina II was demonstrated by BEGAIN deletion. We demonstrated that mechanical allodynia, a condition of abnormal pain induced by innocuous stimuli, in the SNI model was significantly attenuated in BEGAIN-deficient mice. However, there was no significant difference between naive wild-type and BEGAIN-knockout mice in terms of physiological threshold for mechanical stimuli. These results suggest that BEGAIN was involved in pathological pain transmission through NMDA receptor activation by the phosphorylation of GluN2B at Y1472 in spinal inner lamina II.