Inhibition of protein tyrosine phosphatases in spinal dorsal horn attenuated inflammatory pain by repressing Src signaling
Inhibition of protein tyrosine phosphatases in spinal dorsal horn attenuated inflammatory pain by repressing Src signaling
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抑制脊髓背角蛋白酪氨酸磷酸酶通过抑制 Src 信号传导减轻炎症疼痛
DOI：
10.1016/j.neuropharm.2013.01.015
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发表时间：
2013-07
影响因子：
4.7
通讯作者：
Xiao-Dong Hu
中科院分区：
文献类型：
--
作者：
Zhan-Wei Suo;Xian Yang;Lu Li;Yan-Ni Liu;Lei Shi;Xiao-Dong Hu
Src家族蛋白酪氨酸激酶（SFKs）对N-甲基-d-天冬氨酸（NMDA）亚型谷氨酸受体的酪氨酸磷酸化在脊髓致敏中起关键作用。除了SFK，蛋白质的酪氨酸磷酸化水平也由蛋白质酪氨酸磷酸酶（PTPs）决定。然而，PTPs是否参与脊髓伤害性处理在很大程度上是未知的。本研究发现，鞘内应用广谱PTPs抑制剂orthovanadate或Bpv（phen）对完整大鼠对Von Frey细丝刺激的缩爪阈值几乎没有影响。虽然基础伤害性反应不需要PTPs的参与，但鞘内注射NMDA引起的机械性异常性疼痛被原钒酸盐和Bpv（phen）大大减弱，这表明PTPs活性一旦被NMDA受体刺激，就成为脊髓敏化所必需的。生化分析表明PTPs具有激活SFKs成员Src并促进Src与含有NR 2B亚基的NMDA受体（NR 2B受体）相互作用的功能。因此，PTPs抑制在很大程度上抑制Src介导的NR 2B磷酸化Tyr 1472和NMDA处理的大鼠脊髓背角的NR 2B受体的突触浓度降低。重要的是，足底注射完全弗氏佐剂（CFA）自然激活脊髓PTP以启动Src信号传导，因为PTP抑制显著抑制Src活性，减少NR 2B的Src磷酸化，减少NR 2B突触积累并最终改善炎性疼痛。这些数据表明脊髓PTPs在诱导Src依赖性NR 2B受体功能亢进中发挥重要作用，并表明PTPs抑制可能是治疗炎性疼痛的有效策略。
Tyrosine phosphorylation of N-methyl-d-aspartate (NMDA) subtype glutamate receptors by Src-family protein tyrosine kinases (SFKs) plays a critical role in spinal sensitization. Besides SFKs, the tyrosine phosphorylation levels of proteins are also determined by protein tyrosine phosphatases (PTPs). However, whether PTPs are involved in spinal nociceptive processing is largely unknown. The present study found that intrathecal application of broad-spectrum PTPs inhibitors orthovanadate or Bpv (phen) generated little effects on the paw withdrawal thresholds of intact rats to Von Frey filament stimuli. Although the basal nociceptive responses didn't require the involvement of PTPs, the mechanical allodynia evoked by intrathecal injection of NMDA was greatly attenuated by orthovanadate and Bpv (phen), suggesting that PTPs activity, once stimulated by NMDA receptors, became essential for spinal sensitization. Biochemical analysis demonstrated that PTPs functioned to activate SFKs member Src and promote Src interaction with NR2B subunit-containing NMDA receptors (NR2B receptors). As a result, PTPs inhibition largely suppressed Src-mediated NR2B phosphorylation at Tyr1472 and reduced the synaptic concentration of NR2B receptors in spinal dorsal horn of NMDA-treated rats. Importantly, intraplantar injection of Complete Freund's Adjuvant (CFA) naturally activated spinal PTPs to initiate Src signaling, because PTPs inhibition significantly repressed Src activity, reduced Src phosphorylation of NR2B, decreased NR2B synaptic accumulation and eventually ameliorated inflammatory pain. These data indicated an important role played by spinal PTPs in inducing Src-dependent NR2B receptor hyperfunction and suggested that PTPs inhibition might represent an effective strategy for the treatment of inflammatory pain.
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周围炎症增加脊髓背角 NMDA 受体的突触表达
影响因子：
7.4
作者：
Xie, Qin-Jian;Hu, Xiao-Dong;Yang, Hong-Bin;Liu, Xiao-Hua;Yang, Xian
通讯作者：
Yang, Xian
影响因子：
--
作者：
J. Gordon
通讯作者：
J. Gordon
影响因子：
7.4
作者：
Peng, Hsien-Yu;Chen, Gin-Den;Lin, Tzer-Bin
通讯作者：
Lin, Tzer-Bin
DOI：
10.1016/j.bbrc.2005.03.012
发表时间：
2005-05-27
影响因子：
3.1
作者：
Roskoski, R
通讯作者：
Roskoski, R
影响因子：
11.4
作者：
Lei, G;Xue, S;Yu, XM
通讯作者：
Yu, XM