Involvement of calpain/p35-p25/Cdk5/NMDAR signaling pathway in glutamate-induced neurotoxicity in cultured rat retinal neurons.
Involvement of calpain/p35-p25/Cdk5/NMDAR signaling pathway in glutamate-induced neurotoxicity in cultured rat retinal neurons.
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Calpain/p35-p25/Cdk5/NMDAR 信号通路参与谷氨酸诱导的培养大鼠视网膜神经元神经毒性
DOI：
10.1371/journal.pone.0042318
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Miao Y;Dong LD;Chen J;Hu XC;Yang XL;Wang Z
我们研究了钙蛋白酶/p35-p25/细胞周期蛋白依赖性激酶5（Cdk 5）信号通路在谷氨酸诱导的培养大鼠视网膜神经元损伤中可能参与的NMDA受体（NMDARs）修饰。谷氨酸处理降低细胞活力，诱导细胞凋亡，这是伴随着Cdk 5和p-Cdk 5 T15蛋白水平的增加。Cdk 5抑制剂roscovitine可挽救细胞活力并抑制细胞凋亡。此外，钙蛋白酶2和钙蛋白酶特异性α-血影蛋白分解产物（SBDP）的蛋白水平，这两者都是Ca 2+依赖性的，在谷氨酸诱导的细胞损伤中升高。Cdk 5、p-Cdk 5 T15、calpain 2和SBDP蛋白水平随谷氨酸处理时间的延长而下降。此外，SBDP的升高被NMDAR拮抗剂D-APV或非NMDAR拮抗剂CNQX减弱，但几乎不被细胞内钙库抑制剂丹曲林和xestospongin改变。此外，Cdk 5共激活因子p35显著上调，而其裂解产物p25表达显示瞬时增加。谷氨酸处理9 h以内，Cdk 5磷酸化NMDAR亚基NR 2A（p-NR 2AS 1232）和NR 2A（p-NR 2AS 1232/NR 2A）的比例显著增加，并引起p-NR 2AS 1232从胞质向质膜的转位。增强的p-NR 2AS 1232被roscovitine抑制，但被Cdk 5的过表达增强。钙离子成像实验进一步显示，谷氨酸处理2 h、6 h和9 h后，视网膜细胞内钙离子浓度（[Ca 2 +]i）稳定升高。所有这些结果表明，calpain/p35-p25/Cdk 5信号通路的激活可能通过上调p-NR 2AS 1232的表达而促进视网膜中的谷氨酸神经毒性。
We investigated possible involvement of a calpain/p35-p25/cyclin-dependent kinase 5 (Cdk5) signaling pathway in modifying NMDA receptors (NMDARs) in glutamate-induced injury of cultured rat retinal neurons. Glutamate treatment decreased cell viability and induced cell apoptosis, which was accompanied by an increase in Cdk5 and p-Cdk5T15 protein levels. The Cdk5 inhibitor roscovitine rescued the cell viability and inhibited the cell apoptosis. In addition, the protein levels of both calpain 2 and calpain-specific alpha-spectrin breakdown products (SBDPs), which are both Ca2+-dependent, were elevated in glutamate-induced cell injury. The protein levels of Cdk5, p-Cdk5T15, calpain 2 and SBDPs tended to decline with glutamate treatments of more than 9 h. Furthermore, the elevation of SBDPs was attenuated by either D-APV, a NMDAR antagonist, or CNQX, a non-NMDAR antagonist, but was hardly changed by the inhibitors of intracellular calcium stores dantrolene and xestospongin. Moreover, the Cdk5 co-activator p35 was significantly up-regulated, whereas its cleaved product p25 expression showed a transient increase. Glutamate treatment for less than 9 h also considerably enhanced the ratio of the Cdk5-phosphorylated NMDAR subunit NR2A at Ser1232 site (p-NR2AS1232) and NR2A (p-NR2AS1232/NR2A), and caused a translocation of p-NR2AS1232 from the cytosol to the plasma membrane. The enhanced p-NR2AS1232 was inhibited by roscovitine, but augmented by over-expression of Cdk5. Calcium imaging experiments further showed that intracellular Ca2+ concentrations ([Ca2+]i) of retinal cells were steadily increased following glutamate treatments of 2 h, 6 h and 9 h. All these results suggest that the activation of the calpain/p35-p25/Cdk5 signaling pathway may contribute to glutamate neurotoxicity in the retina by up-regulating p-NR2AS1232 expression.
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影响因子：
2.9
作者：
Chiu, K;Lam, TT;Kwong, JMK
通讯作者：
Kwong, JMK
影响因子：
25
作者：
Hawasli, Ammar H.;Benavides, David R.;Bibb, James A.
通讯作者：
Bibb, James A.
影响因子：
4.4
作者：
Guo L;Salt TE;Maass A;Luong V;Moss SE;Fitzke FW;Cordeiro MF
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Cdk5/p35 升高 p-NR2AS1232 导致大鼠实验性青光眼模型中视网膜神经节细胞凋亡
影响因子：
6.1
作者：
Chen, Jie;Miao, Yanying;Wang, Zhongfeng
通讯作者：
Wang, Zhongfeng
影响因子：
25
作者：
Fu, Wing-Yu;Chen, Yu;Ip, Nancy Y.
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Ip, Nancy Y.