Role of AMPA receptors in homocysteine-NMDA receptor-induced crosstalk between ERK and p38 MAPK.
Role of AMPA receptors in homocysteine-NMDA receptor-induced crosstalk between ERK and p38 MAPK.
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DOI：
10.1111/jnc.14078
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发表时间：
2017-08
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;Chen A;Winter L;Rajagopal S;Paul S
同型半胱氨酸是甲硫氨酸循环的代谢产物，它通过激活NMDAR介导的信号通路而发挥神经毒性作用。提出的与同型半胱氨酸-NMDAR诱导的神经毒性相关的机制涉及触发ERK和p38 MAPK之间的串扰的独特信号通路，其中p38 MAPK的激活是ERK MAPK的下游并且依赖于ERK MAPK。然而，ERK MAPK介导的p38 MAPK活化的分子基础尚不清楚。本研究探讨AMPARs是否在促进ERK MAPK介导的p38 MAPK激活中发挥作用。使用表面生物素化和免疫印迹方法，我们表明，治疗与同型半胱氨酸导致表面表达的GluA 2-AMPAR亚基在神经元中的减少，但没有影响表面表达的GluA 1-AMPAR亚基。用D-AP 5抑制NMDAR活化或用PD 98059抑制ERK MAPK磷酸化减弱同型半胱氨酸诱导的GluA 2-AMPAR亚基表面表达的降低。GluA 2-AMPAR亚基表面表达的减少与p38 MAPK磷酸化相关，其被NASPM抑制，NASPM是GluA 2-缺乏Ca 2 +-可渗透AMPAR的选择性拮抗剂。这些结果表明，同型半胱氨酸-NMDAR介导的ERK MAPK磷酸化导致GluA 2-AMPAR亚基表面表达减少，导致Ca 2+通过缺乏GluA 2的Ca 2+渗透性AMPAR内流和p38 MAPK磷酸化。细胞死亡测定进一步显示，用NBQX/CNQX抑制AMPAR活性或用NASPM抑制缺乏GluA 2的Ca 2+可渗透的AMPAR活性减弱了同型半胱氨酸诱导的神经毒性。我们已经确定了一个重要的机制，涉及同型半胱氨酸诱导的神经毒性，突出的中介作用GluA 2缺乏Ca 2+渗透AMPAR的ERK和p38 MAPK之间的串扰。同型半胱氨酸诱导的神经毒性涉及NMDAR介导的ERK和p38 MAPK之间独特串扰的激活。我们在这里报告，ERK MAPK激活导致GluA 2-AMPAR表面表达减少，导致通过GluA 2缺乏Ca 2+渗透性AMPAR增加Ca 2+内流，导致p38 MAPK磷酸化。这些发现揭示了GluA 2缺乏的AMPAR在同型半胱氨酸-NMDAR介导的ERK和p38 MAPK之间的串扰中的重要中介作用。
Homocysteine, a metabolite of the methionine cycle has been reported to play a role in neurotoxicity through activation of NMDAR-mediated signaling pathway. The proposed mechanisms associated with homocysteine-NMDAR induced neurotoxicity involve a unique signaling pathway that triggers a crosstalk between ERK and p38 MAPKs, where activation of p38 MAPK is downstream of and dependent on ERK MAPK. However, the molecular basis of the ERK MAPK mediated p38 MAPK activation is not understood. The current study investigates whether AMPARs play a role in facilitating the ERK MAPK mediated p38 MAPK activation. Using surface biotinylation and immunoblotting approaches we show that treatment with homocysteine leads to a decrease in surface expression of GluA2-AMPAR subunit in neurons, but has no effect on the surface expression of GluA1-AMPAR subunit. Inhibition of NMDAR activation with D-AP5 or ERK MAPK phosphorylation with PD98059 attenuates homocysteine-induced decrease in surface expression of GluA2-AMPAR subunit. The decrease in surface expression of GluA2-AMPAR subunit is associated with p38 MAPK phosphorylation, which is inhibited by NASPM, a selective antagonist of GluA2-lacking Ca2+-permeable AMPARs. These results suggest that homocysteine-NMDAR mediated ERK MAPK phosphorylation leads to a decrease in surface expression of GluA2-AMPAR subunit resulting in Ca2+ influx through the GluA2-lacking Ca2+-permeable AMPARs and p38 MAPK phosphorylation. Cell death assays further show that inhibition of AMPAR activity with NBQX/CNQX or GluA2-lacking Ca2+-permeable AMPAR activity with NASPM attenuates homocysteine-induced neurotoxicity. We have identified an important mechanism involved in homocysteine-induced neurotoxicity that highlights the intermediary role of GluA2-lacking Ca2+-permeable AMPARs in the crosstalk between ERK and p38 MAPKs. Homocysteine-induced neurotoxicity involves NMDAR-mediated activation of a unique crosstalk between ERK and p38 MAPKs. We report here that ERK MAPK activation leads to decrease in GluA2-AMPAR surface expression causing increased Ca2+ influx through GluA2-lacking Ca2+-permeable AMPARs resulting in p38 MAPK phosphorylation. The findings reveal an important intermediary role of GluA2-lacking AMPARs in homocysteine-NMDAR mediated crosstalk between ERK and p38 MAPKs.
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影响因子：
6.1
作者：
Gerace, E.;Masi, A.;Moroni, F.
通讯作者：
Moroni, F.
DOI：
10.1073/pnas.0706447105
发表时间：
2008-01-15
影响因子：
11.1
作者：
Hou, Qingming;Zhang, Dawei;Man, Heng-Ye
通讯作者：
Man, Heng-Ye
影响因子：
2.9
作者：
Cheng, CL;Fass, DM;Reynolds, IJ
通讯作者：
Reynolds, IJ
影响因子：
16.2
作者：
GEIGER, JRP;MELCHER, T;MONYER, H
通讯作者：
MONYER, H
影响因子：
56.9
作者：
Chung, HJ;Steinberg, JP;Linden, DJ
通讯作者：
Linden, DJ