NR2B-NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced neuronal cell death.
NR2B-NMDA receptor mediated modulation of the tyrosine phosphatase STEP regulates glutamate induced neuronal cell death.
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DOI：
10.1111/j.1471-4159.2010.07035.x
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发表时间：
2010-12
影响因子：
4.7
通讯作者：
Paul S
中科院分区：
文献类型：
--
作者：
Poddar R;Deb I;Mukherjee S;Paul S
本研究探讨神经元特异性酪氨酸磷酸酶(STEP)在兴奋性毒性细胞死亡中的作用。我们的发现表明，p38MAPK是STEP的底物，这是一种已知在兴奋性毒性细胞死亡的病因学中发挥作用的应激激活激酶。谷氨酸介导的NMDA受体刺激导致p38MAPK的快速而短暂的激活，这主要依赖于NR2a-NMDA受体的激活。相反，NR2B-NMDA受体的激活导致去磷酸化，继而激活STEP，进而导致p38MAPK的失活。因此，在短暂的NMDA受体刺激中，STEP活性的增加似乎限制了p38MAPK的激活持续时间，并提高了神经元的存活率。然而，如果NR2B-NMDA受体的刺激持续下去，STEP激活的保护作用就会丧失，因为这些刺激会导致活性STEP的显著降解，导致p38 MAP激酶的二次激活。与此观察一致的是，一种与p38MAPK结构性结合的细胞可转导的TAT-Step肽可以减轻持续的NMDA受体刺激引起的神经细胞死亡。这些结果表明，STEP的激活和水平依赖于NR2B-NMDA受体刺激的持续时间和幅度，STEP通过调节p38MAPK而参与NMDA受体依赖性神经元损伤的调节。
The present study examines the role of a neuron-specific tyrosine phosphatase (STEP) in excitotoxic cell death. Our findings demonstrate that p38 MAPK, a stress-activated kinase that is known to play a role in the etiology of excitotoxic cell death is a substrate of STEP. Glutamate-mediated NMDA receptor stimulation leads to rapid but transient activation of p38 MAPK, which is primarily dependent on NR2A-NMDA receptor activation. Conversely, activation of NR2B-NMDA receptors leads to dephosphorylation and subsequent activation of STEP, which in turn leads to inactivation of p38 MAPK. Thus during transient NMDA receptor stimulation, increases in STEP activity appears to limit the duration of activation of p38 MAPK and improves neuronal survival. However, if NR2B-NMDA receptor stimulation is sustained, protective effects of STEP activation are lost, as these stimuli cause significant degradation of active STEP, leading to secondary activation of p38 MAP kinase. Consistent with this observation, a cell transducible TAT-STEP peptide that constitutively binds to p38 MAPK attenuated neuronal cell death caused by sustained NMDA receptor stimulation. The findings imply that the activation and levels of STEP are dependent on the duration and magnitude of NR2B-NMDA receptor stimulation and STEP serves as a modulator of NMDA receptor dependent neuronal injury, through its regulation of p38 MAPK.
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发表时间：
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