NR2B-NMDA receptor-mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP, and ERK MAP kinase signaling.
NR2B-NMDA receptor-mediated increases in intracellular Ca2+ concentration regulate the tyrosine phosphatase, STEP, and ERK MAP kinase signaling.
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DOI：
10.1111/j.1471-4159.2010.06835.x
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发表时间：
2010-08
影响因子：
4.7
通讯作者：
Connor JA
中科院分区：
文献类型：
--
作者：
Paul S;Connor JA
NMDA 受体调节细胞外信号调节激酶 (ERK) 信号级联的激活和失活，这是参与神经元可塑性和存活的关键途径。 NMDA 受体对 ERK 活性的这种双向调节归因于 NR2A 与包含 NR2B 的 NMDA 受体的相反作用，但其如何实现尚不清楚。在这里，我们表明谷氨酸介导的细胞内 Ca2+ 增加分两个阶段发生，首先是快速的初始增加，然后是延迟的较大增加。 Ca2+ 增加的两个阶段均被 MK-801（一种非选择性 NMDA 受体抑制剂）阻断。另一方面，艾芬地尔或 Ro 25-6981 对 NR2B-NMDA 受体的选择性抑制阻断了延迟的较大阶段，但对快速初始增加仅具有很小的影响。 Ca2+ 的初始快速增加（可能是由于 NR2A-NMDAR 激活）足以激活 ERK，而 NR2B-NMDAR 介导的 Ca2+ 的大幅延迟增加对于 STEP 的去磷酸化和随后的激活是必要的，STEP 是一种神经元特异性酪氨酸磷酸酶，进而介导 ERK 的去磷酸化和失活。我们得出的结论是，通过 NR2B-NMDA 受体介导的 Ca2+ 增加的幅度在参与 ERK 活性调节的丝氨酸/苏氨酸和酪氨酸激酶和磷酸酶的调节中起着关键作用。
NMDA receptors regulate both the activation and inactivation of the extracellular signal-regulated kinase (ERK) signaling cascade, a key pathway involved in neuronal plasticity and survival. This bi-directional regulation of ERK activity by NMDA receptors has been attributed to opposing actions of NR2A- versus NR2B-containing NMDA receptors but how this is implemented is not understood. Here we show that glutamate-mediated intracellular Ca2+ increases occur in two phases, a rapid initial increase followed by a delayed larger increase. Both phases of the Ca2+ increase were blocked by MK-801, a non-selective NMDA receptor inhibitor. On the other hand selective inhibition of NR2B-NMDA receptors by Ifenprodil or Ro 25-6981 blocked the delayed larger phase but had only a small effect on the rapid initial increase. The rapid initial increase in Ca2+, presumably due to NR2A-NMDAR activation, was sufficient to activate ERK, whereas the large delayed increases in Ca2+ mediated by NR2B-NMDARs were necessary for dephosphorylation and subsequent activation of STEP, a neuron-specific tyrosine phosphatase that in turn mediates the dephosphorylation and inactivation of ERK. We conclude that the magnitude of Ca2+ increases mediated through NR2B-NMDA receptors plays a critical role in the regulation of the serine/threonine and tyrosine kinases and phosphatases that are involved in the regulation of ERK activity.
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影响因子：
3.6
作者：
Chen, NS;Moshaver, A;Raymond, LA
通讯作者：
Raymond, LA
DOI：
10.1073/pnas.96.22.12866
发表时间：
1999-10-26
影响因子：
11.1
作者：
Alessandrini, A;Namura, S;Bonventre, JV
通讯作者：
Bonventre, JV
影响因子：
3.4
作者：
Braithwaite, Steven P.;Adkisson, Michael;Nikolich, Karoly
通讯作者：
Nikolich, Karoly
影响因子：
4.7
作者：
BENVENISTE, H;DREJER, J;DIEMER, NH
通讯作者：
DIEMER, NH
DOI：
10.1073/pnas.83.16.6179
发表时间：
1986-08-01
影响因子：
11.1
作者：
CONNOR, JA
通讯作者：
CONNOR, JA