Inserm, Unité Mixte de Recherche en Santé 952, F-75005 Paris, France.
J Neurosci. 2011 Oct 5;31(40):14296-307. doi: 10.1523/JNEUROSCI.2890-11.2011.
Activation of the extracellular signal-regulated kinase (ERK) signaling pathway in the striatum is crucial for molecular adaptations and long-term behavioral alterations induced by cocaine. In response to cocaine, ERK controls the phosphorylation levels of both mitogen and stress-activated protein kinase 1 (MSK-1), a nuclear kinase involved in histone H3 (Ser10) and cAMP response element binding protein phosphorylation, and Elk-1, a transcription factor involved in serum response element (SRE)-driven gene regulations. We recently characterized the phenotype of msk-1 knock-out mice in response to cocaine. Herein, we wanted to address the role of Elk-1 phosphorylation in cocaine-induced molecular, morphological, and behavioral responses. We used a cell-penetrating peptide, named TAT-DEF-Elk-1 (TDE), which corresponds to the DEF docking domain of Elk-1 toward ERK and inhibits Elk-1 phosphorylation induced by ERKs without modifying ERK or MSK-1 in vitro. The peptide was injected in vivo before cocaine administration in mice. Immunocytochemical, molecular, morphological, and behavioral studies were performed. The TDE inhibited Elk-1 and H3 (Ser10) phosphorylation induced by cocaine, sparing ERK and MSK-1 activation. Consequently, TDE altered cocaine-induced regulation of genes bearing SRE site(s) in their promoters, including c-fos, zif268, ΔFosB, and arc/arg3.1 (activity-regulated cytoskeleton-associated protein). In a chronic cocaine administration paradigm, TDE reversed cocaine-induced increase in dendritic spine density. Finally, the TDE delayed the establishment of cocaine-induced psychomotor sensitization and conditioned-place preference. We conclude that Elk-1 phosphorylation downstream from ERK is a key molecular event involved in long-term neuronal and behavioral adaptations to cocaine.
细胞外信号调节激酶（ERK）信号通路在纹状体中的激活对于可卡因诱导的分子适应和长期行为改变至关重要。在可卡因的作用下，ERK 控制丝裂原和应激激活蛋白激酶 1（MSK-1）的磷酸化水平，MSK-1 是一种参与组蛋白 H3（Ser10）和 cAMP 反应元件结合蛋白磷酸化的核激酶，以及 Elk-1，一种参与血清反应元件（SRE）驱动的基因调控的转录因子。我们最近描述了 msk-1 敲除小鼠对可卡因的反应表型。在此，我们想要研究 Elk-1 磷酸化在可卡因诱导的分子、形态和行为反应中的作用。我们使用了一种细胞穿透肽，命名为 TAT-DEF-Elk-1（TDE），它对应于 Elk-1 与 ERK 相互作用的 DEF 对接结构域，并抑制 ERK 诱导的 Elk-1 磷酸化，而不改变 ERK 或 MSK-1 在体外的活性。该肽在小鼠给予可卡因前体内注射。进行了免疫细胞化学、分子、形态和行为研究。TDE 抑制了可卡因诱导的 Elk-1 和 H3（Ser10）磷酸化，同时保留了 ERK 和 MSK-1 的激活。因此，TDE 改变了可卡因诱导的基因表达，这些基因的启动子中含有 SRE 位点，包括 c-fos、zif268、ΔFosB 和 arc/arg3.1（活性调节细胞骨架相关蛋白）。在慢性可卡因给药范式中，TDE 逆转了可卡因诱导的树突棘密度增加。最后，TDE 延迟了可卡因诱导的运动敏化和条件性位置偏好的建立。我们的结论是，ERK 下游的 Elk-1 磷酸化是参与可卡因诱导的长期神经元和行为适应的关键分子事件。
