ERK-associated changes of AP-1 proteins during fear extinction
ERK-associated changes of AP-1 proteins during fear extinction
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DOI：
10.1016/j.mcn.2011.03.009
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发表时间：
2011-06-01
影响因子：
3.5
通讯作者：
Radulovic, Jelena
中科院分区：
文献类型：
--
作者：
Guedea, Anita L.;Schrick, Christina;Radulovic, Jelena
广泛的研究已经揭示了学习过程的分子基础，但恐惧消退的机制仍然鲜为人知。当最初引起恐惧的厌恶性刺激不再存在时，情境性恐惧消退发生，并且依赖于细胞外信号调节激酶（ERK）等分子的激活。在这里，我们研究了如何ERK信号触发灭绝影响其下游的目标属于激活蛋白-1（AP-1）转录因子家族。我们发现，灭绝相比，条件的恐惧，显着增强了活性，磷酸化ERK（pERK）与c-Jun的相互作用，导致其磷酸化状态的改变。c-Jun的AP-1结合减少，而JunD的AP-1结合减少。Jun二聚化蛋白2（JDP 2）和ERK表达显著增强。抑制性JunD和JDP 2转录因子的AP-1结合增加被AP-1调节蛋白c-Fos和GluR 2水平降低所抵消。这些变化是特定的灭绝和MEK依赖性。总的来说，恐惧消退涉及ERK/Jun相互作用和AP-1调节蛋白的一个子集的减少，这些蛋白通常是恐惧条件反射所需的。因此，促进抑制性AP-1复合物的形成可能有助于减少恐惧。(C)2011 Elsevier Inc. All rights reserved.
Extensive research has unraveled the molecular basis of learning processes underlying contextual fear conditioning, but the mechanisms of fear extinction remain less known. Contextual fear extinction occurs when an aversive stimulus that initially caused fear is no longer present and depends on the activation of the extracellular signal-regulated kinase (ERK), among other molecules. Here we investigated how ERK signaling triggered by extinction affects its downstream targets belonging to the activator protein-1 (AP-1) transcription factor family. We found that extinction, when compared to conditioning of fear, markedly enhanced the interactions of active, phospho-ERK (pERK) with c-Jun causing alterations of its phosphorylation state. The AP-1 binding of c-Jun was decreased whereas AP-1 binding of JunD. Jun dimerization protein 2 (JDP2) and ERK were significantly enhanced. The increased AP-1 binding of the inhibitory JunD and JDP2 transcription factors was paralleled by decreased levels of the AP-1 regulated proteins c-Fos and GluR2. These changes were specific for extinction and were MEK-dependent. Overall, fear extinction involves ERK/Jun interactions and a decrease of a subset of AP-1-regulated proteins that are typically required for fear conditioning. Facilitating the formation of inhibitory AP-1 complexes may thus facilitate the reduction of fear. (C) 2011 Elsevier Inc. All rights reserved.