De Novo Protein Synthesis Mediated by the Eukaryotic Elongation Factor 2 Is Required for the Anxiolytic Effect of Oxytocin
De Novo Protein Synthesis Mediated by the Eukaryotic Elongation Factor 2 Is Required for the Anxiolytic Effect of Oxytocin
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DOI：
10.1016/j.biopsych.2019.01.010
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发表时间：
2019-05-15
影响因子：
10.6
通讯作者：
Neumann, Inga D.
中科院分区：
文献类型：
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作者：
Martinetz, Stefanie;Meinung, Carl-Philipp;Neumann, Inga D.
背景：神经肽催产素（OXT）通过其G蛋白偶联的OXT受体介导其作用，包括抗焦虑作用。在下丘脑室旁核（PVN）内，OXT诱导的抗焦虑作用至少部分是通过激活丝裂原活化蛋白激酶途径介导的，随后钙通过瞬时受体电位阳离子通道亚家族V成员2通道内流。在外周，OXT激活真核细胞延伸因子2（eEF 2），eEF 2是蛋白质合成的重要介质。方法：为了研究OXT是否也激活神经元中的eEF 2以在PVN中发挥其抗焦虑特性，我们进行了体内和细胞培养实验。我们证明，OXT，在蛋白激酶C依赖的方式，激活eEF2在下丘脑细胞系和在体内的PVN内。接下来，我们揭示了OXT刺激从头蛋白质合成，而抑制PVN内的蛋白质合成阻止了OXT在雄性大鼠中的抗焦虑作用。此外，PVN内eEF 2的激活传达了抗焦虑作用，支持OXT诱导的eEF 2激活和蛋白质合成的抗焦虑作用。最后，我们表明，由OXT上调的蛋白质之一是神经肽Y受体5。将特定的神经肽Y受体5激动剂输注到PVN中，从而导致焦虑相关行为减少，而用神经肽Y受体5拮抗剂预处理可防止OXT的抗焦虑作用。总之，这些结果表明，OXT募集几个细胞内信号级联来诱导蛋白质合成，其在PVN内介导OXT的抗焦虑作用，并表明eEF 2代表焦虑相关疾病的新靶点。
BACKGROUND: The neuropeptide oxytocin (OXT) mediates its actions, including anxiolysis, via its G protein-coupled OXT receptor. Within the paraventricular nucleus of the hypothalamus (PVN), OXT-induced anxiolysis is mediated, at least in part, via activation of the mitogen-activated protein kinase pathway following calcium influx through transient receptor potential cation channel subfamily V member 2 channels. In the periphery, OXT activates eukaryotic elongation factor 2 (eEF2), an essential mediator of protein synthesis.METHODS: In order to study whether OXT activates eEF2 also in neurons to exert its anxiolytic properties in the PVN, we performed in vivo and cell culture experiments.RESULTS: We demonstrate that OXT, in a protein kinase C-dependent manner, activates eEF2 both in a hypothalamic cell line and in vivo within the PVN. Next, we reveal that OXT stimulates de novo protein synthesis, while inhibition of protein synthesis within the PVN prevents the anxiolytic effect of OXT in male rats. Moreover, activation of eEF2 within the PVN conveyed an anxiolytic effect supporting a role of OXT-induced eEF2 activation and protein synthesis for its anxiolysis. Finally, we show that one of the proteins that is upregulated by OXT is the neuropeptide Y receptor 5. Infusion of a specific neuropeptide Y receptor 5 agonist into the PVN consequently led to decreased anxiety-related behavior, while pretreatment with a neuropeptide Y receptor 5 antagonist prevented the anxiolytic effect of OXT.CONCLUSIONS: Taken together, these results show that OXT recruits several intracellular signaling cascades to induce protein synthesis, which mediates the anxiolytic effects of OXT within the PVN and suggests that eEF2 represents a novel target for anxiety-related disorders.