蛋白酪氨酸磷酸酶(PTPs)，通过降低底物的磷酸化水平，控制着一系列病理生理过程。在脊髓背角，抑制PTPs的活性，会阻断痛觉的突触传递、有效缓解病理性疼痛症状，提示：某些PTPs可能具有"兴奋性"的痛觉调控作用。但究竟哪些PTPs、以何种机制参与痛觉敏感化的形成，目前尚不清楚。申请者的预实验，从众多表达于脊髓背角的PTPs分子中，首次鉴定并发现：一种分布于内质网的酪氨酸磷酸酶PTP1B(Protein Tyrosine Phosphatase 1B)，能够正性调节Src家族酪氨酸激酶的活性，特异性增强"包含NR2B亚基的NMDA受体"介导的痛觉突触传递；而内质网中的PTP1B之所以能够进入突触、实现对NR2B的靶向性调节，可能与一种膜相关鸟苷酸激酶SAP102的引导有关。基于此，本项目提出以下假设：酪氨酸磷酸酶PTP1B可能以SAP102为桥梁，启动Src/NR2B通路，诱发病理性疼痛。

Protein Tyrosine Phosphatases (PTPs) control a series of pathophysiological processes by reducing the phosphorylation levels of substrates. In spinal dorsal horn, inhibition of PTPs is able to block the synaptic transmission of nociceptive signals and produce effective analgesia against pathological pain, suggesting that some PTPs might exert "excitatory" regulation of nociceptive conveyance. However, either the identities of PTPs or the mechanisms by which they exacerbate pain sensitization are largely unknown as yet. Our preliminary experiment tested a line of PTPs members expressed in spinal dorsal horn, and revealed for the first time that PTP1B, a protein tyrosine phosphatase that localizes at endoplasmic reticulum (ER), positively regulated the activity of Src family protein tyrosine kinases and selectively potentiated the nociceptive synaptic transmission mediated by NR2B subunit-containing NMDA receptors. The entry of ER-bound PTP1B into synapses might require the membrane-associated guanylate kinases (MAGUKs) SAP102, which possibly targeted PTP1B to synaptic NR2B receptors. Based on these observations, the applicants proposed the hypothesis that protein tyrosine phosphatase PTP1B, by the aid of SAP102, might initiate Src/NR2B signaling to evoke pathological pain.