Disruption of SHP1/NMDA receptor signaling in spinal cord dorsal horn alleviated inflammatory pain
Disruption of SHP1/NMDA receptor signaling in spinal cord dorsal horn alleviated inflammatory pain
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脊髓背角 SHP1/NMDA 受体信号传导的破坏可减轻炎性疼痛
DOI：
10.1016/j.neuropharm.2018.04.029
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发表时间：
2018-07
影响因子：
4.7
通讯作者：
Hu Xiao-Dong
中科院分区：
文献类型：
--
作者：
Yang Li;Bai Hu-Hu;Zhang Zi-Yang;Liu Jiang-Ping;Suo Zhan-Wei;Yang Xian;Hu Xiao-Dong
含Src同源2结构域的蛋白酪氨酸磷酸酶-1（SHP 1）是一种在造血细胞中高度富集的非受体样磷酸酶。虽然越来越多的证据表明蛋白酪氨酸磷酸酶参与了伤害性信息传递和可塑性的调节，但SHP 1是否在疼痛相关的脊髓背角表达并参与伤害性信息的突触修饰尚不清楚。在这里，我们发现，SHP 1是存在于大鼠脊髓神经元和功能耦合到谷氨酸受体的GluN 2A亚基含有N-甲基-d-天冬氨酸亚型，在中枢致敏的伤害性行为的关键球员之一。SHP 1与GluN 2A胞质尾内的近膜区域相互作用。这种相互作用是刺激SHP 1活性所必需的，更重要的是，限制SHP 1信号传导以特异性增强炎症疼痛期间GluN 2A的酪氨酸磷酸化。电生理和行为学研究表明，SHP 1结合增强GluN 2A电流和诱发GluN 2A依赖性疼痛超敏反应。siRNA介导的SHP 1敲低或通过合成肽干扰SHP 1/GluN 2A相互作用减轻了完全弗氏佐剂或福尔马林诱导的炎性疼痛。我们的数据表明，SHP 1是一个特定的增强剂的GluN 2A介导的伤害性突触传递在脊髓背角，和操纵SHP 1的活性可能是一种有效的策略，治疗炎症性疼痛。
Src-homology 2 domain-containing protein tyrosine phosphatase-1 (SHP1) is one of the non-receptor-like phosphatases that are highly enriched in hematopoietic cells. Although accumulating evidence has implicated the protein tyrosine phosphatases in the regulation of nociceptive transmission and plasticity, it is largely unknown whether SHP1 was expressed in pain-related spinal cord dorsal horn and engaged in the synaptic modification of nociceptive signals. Here we found that SHP1 was present in spinal neurons of rats and functionally coupled to GluN2A subunit-containing N-methyl-d-aspartate subtype of glutamate receptors, one of the key players in central sensitization of nociceptive behaviors. SHP1 interacted with a membrane-proximal region within the cytoplasmic tail of GluN2A. This interaction was necessary to stimulate SHP1 activity and more importantly, restrict SHP1 signaling to specifically enhance the tyrosine phosphorylation of GluN2A during inflammatory pain. Electrophysiological and behavioral studies showed that SHP1 binding potentiated GluN2A currents and evoked GluN2A-dependent pain hypersensitivity. The siRNA-mediated knockdown of SHP1 or interference with SHP1/GluN2A interaction by a synthetic peptide alleviated inflammatory pain induced by either Complete Freund's Adjuvant or formalin. Our data implicated that SHP1 was a specific enhancer of GluN2A-mediated nociceptive synaptic transmission in spinal cord dorsal horn, and manipulation of SHP1 activity may serve as an effective strategy for the treatment of inflammatory pain.
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影响因子：
8.7
作者：
Lorenz U
通讯作者：
Lorenz U
影响因子：
16.2
作者：
Hayashi, Takashi;Thomas, Gareth M.;Huganir, Richard L.
通讯作者：
Huganir, Richard L.
影响因子：
2.8
作者：
Lopez-Ruiz, Pilar;Rodriguez-Ubreva, Javier;Colas, Begona
通讯作者：
Colas, Begona
影响因子：
3
作者：
Thomas-Crusells, J;Vieira, A;Rivera, C
通讯作者：
Rivera, C
影响因子：
7.4
作者：
Peng, Hsien-Yu;Chen, Gin-Den;Lin, Tzer-Bin
通讯作者：
Lin, Tzer-Bin