Dopamine promotes striatal neuronal apoptotic death via ERK signaling cascades.
Dopamine promotes striatal neuronal apoptotic death via ERK signaling cascades.
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DOI：
10.1111/j.1460-9568.2008.06590.x
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发表时间：
2009-01
期刊：
影响因子：
--
通讯作者：
Sidhu A
中科院分区：
文献类型：
--
作者：
Chen J;Rusnak M;Lombroso PJ;Sidhu A
虽然纹状体神经变性的机制尚不清楚，但我们已经证明纹状体的发病机制可能是由高突触水平的细胞外多巴胺(DA)启动的。在这里，我们研究了在大鼠纹状体原代神经元中，DA处理后丝裂原活化蛋白激酶(MAPK)信号通路的动员。我们没有观察到典型的亲细胞毒性MAPKs、p-JNK和p-p38MAPK的升高，而是发现DA通过D1DA受体通过cAMP/PKA/Rap1/B-Raf/MEK通路诱导细胞外信号调节激酶(p-ERK)的磷酸化形式的持续刺激。用受体特异性拮抗剂阻断D2DA受体、β肾上腺素能受体或NMDA型受体对此过程无明显影响。DA激活D1DA受体和PKA导致纹状体富含酪氨酸磷酸酶(STEP)的磷酸化和失活，STEP是纹状体p-ERK去磷酸化和随后失活的重要磷酸酶。有趣的是，p-ERK主要保留在细胞质中，只有少量转移到细胞核。支架蛋白β-arrestin2与p-ERK和D1DA受体相互作用，触发p-ERK的胞浆滞留，诱导纹状体神经元的凋亡。这些数据为p-ERK在纹状体神经退行性变中的新作用提供了独特的见解。
Although the mechanisms underlying striatal neurodegeneration are poorly understood, we have shown that striatal pathogenesis may be initiated by high synaptic levels of extracellular dopamine (DA). Here we investigated in rat striatal primary neurons the mobilization of the mitogen activated protein kinase (MAPK) signaling pathways after treatment with DA. Instead of observing an elevation of the archetypical pro-cytotoxic MAPKs, p-JNK and p-p38 MAPK, we found that DA, acting through D1 DA receptors, induced a sustained stimulation of the phosphorylated form of extracellular signal-regulated kinase (p-ERK) via a cAMP/PKA/Rap1/B-Raf/MEK pathway. Blockade of D2 DA receptors, β-adrenergic receptors or NMDA receptors with receptor-specific antagonists had no significant effect on this process. Activation of D1 DA receptors and PKA by DA caused phosphorylation and inactivation of the striatal–enriched tyrosine phosphatase (STEP), an important phosphatase for the dephosphorylation and subsequent inactivation of p-ERK in striatum. Interestingly p-ERK was primarily retained in the cytoplasm, with only low amounts translocated to the nucleus. The scaffold protein β-arrestin2 interacted with both p-ERK and D1 DA receptor, triggering the cytosolic retention of p-ERK and inducing striatal neuronal apoptotic death. These data provide unique insight into a novel role of p-ERK in striatal neurodegeneration.
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影响因子：
3.4
作者：
Cepeda, C;Colwell, CS;Levine, MS
通讯作者：
Levine, MS
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：
11.4
作者：
Brunet, A;Roux, D;Pouysségur, J
通讯作者：
Pouysségur, J
影响因子：
64.8
作者：
Chang, LF;Karin, M
通讯作者：
Karin, M
影响因子：
3.4
作者：
Andringa, G;Stoof, JC;Cools, AR
通讯作者：
Cools, AR