Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine-NMDA receptor-mediated neuronal cell death.
Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine-NMDA receptor-mediated neuronal cell death.
复制标题
DOI：
10.1111/jnc.12102
复制
发表时间：
2013-02
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;Paul S
高同型半胱氨酸血症是急性和慢性神经系统疾病的一个独立危险因素，但人们对高同型半胱氨酸升高促进神经元细胞死亡的潜在机制知之甚少。我们最近建立了NMDA受体介导的细胞外信号调节激酶-有丝分裂原激活蛋白激酶（ERK-MAPK）在同型半胱氨酸诱导的神经细胞死亡中的作用。在本研究中，我们研究了应激诱导的MAPK，p38在同型半胱氨酸诱导的神经元细胞死亡的参与，并进一步探讨了两个MAPK，ERK和p38，在触发细胞死亡之间的关系。同型半胱氨酸介导的NMDA受体刺激和随后的Ca 2+内流导致p38 MAPK的双相激活，其特征在于初始快速但短暂的激活，随后是延迟和更长时间的反应。选择性抑制延迟p38 MAPK活性足以减弱同型半胱氨酸诱导的神经元细胞死亡。使用药理学和RNAi方法，我们进一步证明了p38 MAPK的初始和延迟激活都是ERK MAPK激活的下游，并依赖于ERK MAPK的激活。我们的研究结果强调了一种新的ERK和p38 MAPK之间的相互作用，在同型半胱氨酸-NMDA受体诱导的神经元细胞死亡。
Hyperhomocysteinemia is an independent risk factor for both acute and chronic neurological disorders but little is known about the underlying mechanisms by which elevated homocysteine can promote neuronal cell death. We recently established a role for NMDA receptor mediated activation of extracellular signal-regulated kinase-mitogen activated protein kinase (ERK-MAPK) in homocysteine-induced neuronal cell death. In the present study we examined the involvement of the stress-induced MAPK, p38 in homocysteine-induced neuronal cell death and further explored the relationship between the two MAPKs, ERK and p38, in triggering cell death. Homocysteine mediated NMDA receptor stimulation and subsequent Ca2+ influx led to a biphasic activation of p38 MAPK characterized by an initial rapid but transient activation followed by a delayed and more prolonged response. Selective inhibition of the delayed p38 MAPK activity was sufficient to attenuate homocysteine-induced neuronal cell death. Using pharmacological and RNAi approaches we further demonstrated that both the initial and delayed activation of p38 MAPK is downstream of, and dependent on activation of ERK MAPK. Our findings highlight a novel interplay between ERK and p38 MAPK in homocysteine-NMDA receptor induced neuronal cell death.
登录
查看更多内容
影响因子：
5.3
作者：
Liu, Yitao;Wong, Tak Pan;Wang, Yu Tian
通讯作者：
Wang, Yu Tian
影响因子：
25
作者：
Li, B;Chen, NS;Raymond, LA
通讯作者：
Raymond, LA
影响因子：
4.4
作者：
Ganapathy, Preethi S.;Perry, Richard L.;Smith, Sylvia B.
通讯作者：
Smith, Sylvia B.
影响因子：
16.2
作者：
Ehlers, MD
通讯作者：
Ehlers, MD
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM