Gain control of N-methyl-D-aspartate receptor activity by receptor-like protein tyrosine phosphatase α
Gain control of N-methyl-D-aspartate receptor activity by receptor-like protein tyrosine phosphatase α
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DOI：
10.1093/emboj/cdf292
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发表时间：
2002-06-17
期刊：
影响因子：
11.4
通讯作者：
Yu, XM
中科院分区：
文献类型：
--
作者：
Lei, G;Xue, S;Yu, XM
研究发现，Src 激酶对中枢神经系统 (CNS) 中 N-甲基-D-天冬氨酸 (NMDA) 亚型谷氨酸受体的调节在与学习和记忆、乙醇敏感性和癫痫相关的过程中发挥着重要作用。然而，人们对 Src 家族激酶活性控制 NMDA 受体的调节机制知之甚少。在这里，我们报道蛋白酪氨酸磷酸酶α（PTPα）的远端磷酸酶结构域（D2）与突触后密度95（PSD95）的PDZ2结构域结合。因此，Src 激酶、其激活剂 (PTPα) 和底物（NMDA 受体）通过相同的支架蛋白 PSD95 连接。 PTPalpha 的去除不会影响 Src 与 NMDA 受体的结合，但会关闭激酶对 NMDA 受体的组成性调节。此外，我们发现将 PTPα 催化结构域 (D1 + D2) 应用到神经元中可以增强 NMDA 受体介导的突触反应。相反，内源性 PTPα 的阻断会抑制 NMDA 受体活性和海马神经元长时程增强的诱导。因此，PTPalpha 是中枢神经系统突触强度的新型上调剂。
Src kinase regulation of N-methyl-D-aspartate (NMDA) subtype glutamate receptors in the central nervous system (CNS) has been found to play an important role in processes related to learning and memory, ethanol sensitivity and epilepsy. However, little is known regarding the mechanisms underlying the regulation of Src family kinase activity in the control of NMDA receptors. Here we report that the distal phosphatase domain (D2) of protein tyrosine phosphatase alpha (PTPalpha) binds to the PDZ2 domain of post-synaptic density 95 (PSD95). Thus, Src kinase, its activator (PTPalpha) and substrate (NMDA receptors) are linked by the same scaffold protein, PSD95. Removal of PTPalpha does not affect the association of Src with NMDA receptors, but turns off the constitutive regulation of NMDA receptors by the kinase. Furthermore, we found that application of the PTPalpha catalytic domains (D1 + D2) into neurones enhances NMDA receptor-mediated synaptic responses. Conversely, the blockade of endogenous PTPalpha inhibits NMDA receptor activity and the induction of long-term potentiation in hippocampal neurones. Thus, PTPalpha is a novel up-regulator of synaptic strength in the CNS.