NR2B Phosphorylation at Tyrosine 1472 in Spinal Dorsal Horn Contributed to N-Methyl-D-Aspartate-Induced Pain Hypersensitivity in Mice
NR2B Phosphorylation at Tyrosine 1472 in Spinal Dorsal Horn Contributed to N-Methyl-D-Aspartate-Induced Pain Hypersensitivity in Mice
复制标题
NR2B 脊髓背角酪氨酸 1472 处的磷酸化导致 N-甲基-D-天冬氨酸诱导的小鼠疼痛超敏反应
DOI：
10.1002/jnr.22719
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发表时间：
2011-11-01
影响因子：
4.2
通讯作者：
Hu, Xiao-Dong
中科院分区：
文献类型：
--
作者：
Li, Shuai;Cao, Jing;Hu, Xiao-Dong
钙通过 N-甲基-D-天冬氨酸 (NMDA) 亚型谷氨酸受体 (NMDAR) 流入调节 NMDAR 的细胞内运输，从而导致 NMDAR 介导的突触传递发生持久改变，从而参与发育、学习和突触可塑性。本研究调查了脊髓背角中这种 NMDAR 依赖性突触运输对诱导疼痛超敏反应的贡献。我们的数据表明，鞘内应用 NMDA 直接激活 NMDAR 会在完整小鼠中引起明显的机械异常性疼痛，同时突触后密度 (PSD) 富集部分的 NMDAR 亚基 NR1 和 NR2B 丰度发生特异性增加。艾芬地尔对含有 NR2B 的 NMDAR (NR2BR) 的选择性抑制可剂量依赖性地减轻注射 NMDA 的小鼠的机械异常性疼痛，这表明 NR2BR 突触积累在 NMDA 诱导的疼痛敏化中的重要性。 NMDA 攻击后突触上的 NR2BR 重新分布与 Tyr1472 处 NR2B 磷酸化的显着增加相关，Tyr1472 是 Src 家族蛋白酪氨酸激酶 (SFK) 的催化位点，已被证明可以阻止 NR2B 内吞作用。鞘内注射特定的 SFK 抑制剂 PP2 来阻断 NR2B 酪氨酸磷酸化，消除了 NMDA 诱导的 NR2BR 突触表达，并减轻了机械性异常性疼痛。这些数据表明，脊髓 NMDAR 的激活能够通过 SFK 信号在突触处积累 NR2BR，这可能会夸大 NMDAR 依赖性伤害性传递，并导致 NMDA 诱导的伤害性行为高反应性。 (C) 2011 Wiley-Liss, Inc.
Calcium influx via N-methyl-D-aspartate (NMDA)-subtype glutamate receptors (NMDARs) regulates the intracellular trafficking of NMDARs, leading to long-lasting modification of NMDAR-mediated synaptic transmission that is involved in development, learning, and synaptic plasticity. The present study investigated the contribution of such NMDAR-dependent synaptic trafficking in spinal dorsal horn to the induction of pain hypersensitivity. Our data showed that direct activation of NMDARs by intrathecal NMDA application elicited pronounced mechanical allodynia in intact mice, which was concurrent with a specific increase in the abundance of NMDAR subunits NR1 and NR2B at the postsynaptic density (PSD)-enriched fraction. Selective inhibition of NR2B-containing NMDARs (NR2BR) by ifenprodil dose dependently attenuated the mechanical allodynia in NMDA-injected mice, suggesting the importance of NR2BR synaptic accumulation in NMDA-induced pain sensitization. The NR2BR redistribution at synapses after NMDA challenge was associated with a significant increase in NR2B phosphorylation at Tyr1472, a catalytic site by Src family protein tyrosine kinases (SFKs) that has been shown to prevent NR2B endocytosis. Intrathecal injection of a specific SFKs inhibitor, PP2, to block NR2B tyrosine phosphorylation eliminated NMDA-induced NR2BR synaptic expression and also attenuated the mechanical allodynia. These data suggested that activation of spinal NMDARs was able to accumulate NR2BR at synapses via SFK signaling, which might exaggerate NMDAR-dependent nociceptive transmission and contribute to NMDA-induced nociceptive behavioral hyperresponsiveness. (C) 2011 Wiley-Liss, Inc.