The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling
The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling
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MT2 受体通过激活 Akt 信号传导刺激轴突发生并增强突触传递
DOI：
10.1038/cdd.2014.195
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发表时间：
2015-04-01
影响因子：
12.4
通讯作者：
Wang, J-Z
中科院分区：
文献类型：
--
作者：
Liu, D.;Wei, N.;Wang, J-Z
MT 2受体是G蛋白偶联受体的主要类型，其主要介导褪黑激素的作用。褪黑激素/MT 2信号传导的缺陷已经在许多神经系统疾病中发现，包括阿尔茨海默病，老年痴呆症的最常见原因，这表明MT 2受体的保留可能对这些神经系统疾病有益。然而，将MT 2受体与认知相关的突触可塑性联系起来的直接证据仍有待建立。在这里，我们报告的MT 2受体，而不是MT 1受体，是必不可少的轴突在体外和体内。我们发现，轴突形成在MT 2受体敲除小鼠，MT 2-shRNA电穿孔的脑切片或用MT 2受体选择性拮抗剂处理的原代神经元中延迟。MT 2受体的激活促进轴突发生，其与中枢神经元中兴奋性突触传递的增强相关。MT 2受体下游的信号传导组分由Akt/GSK-3 β/CRMP-2级联组成。MT 2受体C-末端基序直接与Akt结合。MT 2受体的抑制或MT 2受体-Akt结合的破坏减少了轴突发生和突触传递。我们的数据表明，MT 2受体激活Akt/GSK-3 β/CRMP-2信号，是必要的，足以介导中枢神经元中的功能性轴突生成和突触形成。
The MT2 receptor is a principal type of G protein-coupled receptor that mainly mediates the effects of melatonin. Deficits of melatonin/MT2 signaling have been found in many neurological disorders, including Alzheimer's disease, the most common cause of dementia in the elderly, suggesting that preservation of the MT2 receptor may be beneficial to these neurological disorders. However, direct evidence linking the MT2 receptor to cognition-related synaptic plasticity remains to be established. Here, we report that the MT2 receptor, but not the MT1 receptor, is essential for axonogenesis both in vitro and in vivo. We find that axon formation is retarded in MT2 receptor knockout mice, MT2-shRNA electroporated brain slices or primary neurons treated with an MT2 receptor selective antagonist. Activation of the MT2 receptor promotes axonogenesis that is associated with an enhancement in excitatory synaptic transmission in central neurons. The signaling components downstream of the MT2 receptor consist of the Akt/GSK-3 beta/CRMP-2 cascade. The MT2 receptor C-terminal motif binds to Akt directly. Either inhibition of the MT2 receptor or disruption of MT2 receptor-Akt binding reduces axonogenesis and synaptic transmission. Our data suggest that the MT2 receptor activates Akt/GSK-3 beta/CRMP-2 signaling and is necessary and sufficient to mediate functional axonogenesis and synaptic formation in central neurons.