Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain
Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain
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DOI：
10.1111/j.1460-9568.2005.04340.x
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发表时间：
2005-09-01
影响因子：
3.4
通讯作者：
Ito, S
中科院分区：
文献类型：
--
作者：
Abe, T;Matsumura, S;Ito, S
尽管有大量证据表明脊髓中N-甲基-D-天冬氨酸（NMDA）受体对疼痛传递的重要性，但对于持续数周的神经性疼痛状态，与NMDA受体活化偶联的信号转导在很大程度上是未知的。为了解决这一问题，我们通过切断脊神经L5制备了具有神经性疼痛的小鼠。野生型、NR 2A缺陷型和NR 2D缺陷型小鼠发生神经性疼痛;此外，在神经损伤后1周，在脊髓浅层背角观察到NMDA受体的NR 2B亚基在Tyr 1472处的磷酸化。NR 2B选择性拮抗剂CP-101，606可减弱神经病理性疼痛和NR 2B在Tyr 1472处的磷酸化，并在缺乏Fyn激酶（一种Src家族酪氨酸激酶）的小鼠中消失。伴随着NR 2B磷酸化，神经元型一氧化氮合酶活性增加可视化在神经病理性疼痛小鼠的背角浅层NADPH黄递酶组织化学。电镜观察发现，神经病理性疼痛小鼠脊髓中磷酸化的NR 2B定位于突触后致密区。前列腺素（PG）合成抑制剂吲哚美辛和前列腺素E受体亚型EP 1选择性拮抗剂降低了这些小鼠中NR 2B的磷酸化。相反，EP 1选择性激动剂刺激Fyn激酶依赖的一氧化氮在脊髓中的形成。目前的研究表明，酪氨酸1472磷酸化的NR 2B亚基的Fyn激酶可能有双重作用，在保留的NMDA受体在突触后密度和激活一氧化氮合酶，并建议PGE（2）参与维持神经病理性疼痛通过EP 1亚型。
Despite abundant evidence implicating the importance of N-methyl-D-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE(2) is involved in the maintenance of neuropathic pain via the EP1 subtype.