Reduced NMDA receptor tyrosine phosphorylation in PTPα-deficient mouse synaptosomes is accompanied by inhibition of four src family kinases and Pyk2:: an upstream role for PTPα in NMDA receptor regulation
Reduced NMDA receptor tyrosine phosphorylation in PTPα-deficient mouse synaptosomes is accompanied by inhibition of four src family kinases and Pyk2:: an upstream role for PTPα in NMDA receptor regulation
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DOI：
10.1111/j.1471-4159.2006.04075.x
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发表时间：
2006-09-01
影响因子：
4.7
通讯作者：
Pallen, Catherine J.
中科院分区：
文献类型：
--
作者：
Le, Hoa T.;Maksumova, Lola;Pallen, Catherine J.
缺乏蛋白酪氨酸磷酸酶α(PTPα)的小鼠在NMDAR相关过程中表现出缺陷，如学习和记忆、海马神经元迁移和CA1海马长时程增强(LTP)。在体内连接PTPα和NMDAR的分子效应器尚未见报道。因此，在野生型和PTPα缺失小鼠的突触体内，研究了PTPα作为NMDAR酪氨酸磷酸化上游调节因子的作用。在PTPα消融时，NMDAR NR2A和NR2B亚基的酪氨酸磷酸化水平降低，这表明该磷酸酶通过中间分子对NMDAR的磷酸化起到积极的作用。NMDAR是src家族酪氨酸激酶的底物，在缺乏PTPα的情况下，src、fyn、yes和lck的活性明显降低，但Lyn的活性没有明显降低。此外，在PTPα缺陷的突触体中，富含脯氨酸的酪氨酸激酶2(PYK2)的自磷酸化也减少。在PTPα缺失小鼠发育的任何阶段，蛋白酪氨酸磷酸化改变并不伴随NMDAR或上述酪氨酸激酶表达的改变。在人胚胎肾(HEK)293细胞表达系统中，PTPα使fyn介导的NR2A和NR2B酪氨酸磷酸化增加数倍。总之，这些发现提供了证据，证明PTPα缺失小鼠异常的NMDAR相关功能是由于可能不止一种src家族激酶src、fyn、yes和lck的活性降低导致的NMDAR酪氨酸磷酸化受损所致。这些小鼠的NMDAR活性缺陷也可能与作为Pyk2上游调节因子的PTPα的丢失有关。
Mice lacking protein tyrosine phosphatase alpha (PTP alpha) exhibited defects in NMDA receptor (NMDAR)-associated processes such as learning and memory, hippocampal neuron migration, and CA1 hippocampal long-term potentiation (LTP). In vivo molecular effectors linking PTP alpha and the NMDAR have not been reported. Thus the involvement of PTP alpha as an upstream regulator of NMDAR tyrosine phosphorylation was investigated in synaptosomes of wild-type and PTP alpha-null mice. Tyrosine phosphorylation of the NMDAR NR2A and NR2B subunits was reduced upon PTP alpha ablation, indicating a positive effect of this phosphatase on NMDAR phosphorylation via intermediate molecules. The NMDAR is a substrate of src family tyrosine kinases, and reduced activity of src, fyn, yes and lck, but not lyn, was apparent in the absence of PTP alpha. In addition, autophosphorylation of proline-rich tyrosine kinase 2 (Pyk2), a tyrosine kinase linked to NMDAR signaling, was also reduced in PTP alpha-deficient synaptosomes. Altered protein tyrosine phosphorylation was not accompanied by altered expression of the NMDAR or the above tyrosine kinases at any stage of PTP alpha-null mouse development examined. In a human embryonic kidney (HEK) 293 cell expression system, PTP alpha enhanced fyn-mediated NR2A and NR2B tyrosine phosphorylation by several-fold. Together, these findings provide evidence that aberrant NMDAR-associated functions in PTP alpha-null mice are due to impaired NMDAR tyrosine phosphorylation resulting from the reduced activity of probably more than one of the src family kinases src, fyn, yes and lck. Defective NMDAR activity in these mice may also be linked to the loss of PTP alpha as an upstream regulator of Pyk2.