NK 1R/5-HT1AR interaction is related to the regulation of melanogenesis
NK 1R/5-HT1AR interaction is related to the regulation of melanogenesis
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NK 1R/5-HT1AR相互作用与黑色素生成的调节有关
DOI：
10.1096/fj.201700564rr
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Shang Jing
中科院分区：
文献类型：
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作者：
Wu Huali;Zhao Yucheng;Huang Qiaoling;Cai Minxuan;Pan Qi;Fu Mengsi;An Xiaohong;Xia Zhenjiang;Liu Meng;Jin Yu;He Ling;Shang Jing
P物质（SP）是脑-皮肤轴沿着的候选介质，可以模拟应激的作用来调节黑素生成。以前，我们和其他人发现SP对色素功能的调节是由神经激肽1受体（NK 1 R）介导的。越来越多的证据表明，心理应激可诱导皮肤5-羟色胺（5-HT）-5-HT 1A/1B受体系统功能障碍，从而导致皮肤色素减退。此外，NK 1 R和5-HTR（5-HT 3除外）属于GPCR。本研究旨在评估可能存在的NK 1 R-5-HTR相互作用和相关的黑素生成功能。Western blot和PCR检测显示SP可降低5-HT 1A受体和NK 1受体的表达。生化分析表明，NK 1 R和5-HT 1AR可以在细胞和皮肤中共定位并相互作用。当NK 1 R蛋白的N端被去除时，NK 1 R表面靶向被阻止，NK 1 R-5-HT 1AR之间的相互作用降低，并且可以挽救SP和WAY 100635引起的脱色。重要的是，NK 1 R激动剂（SP）和5-HT 1A拮抗剂（WAY 100635）的药物联合给药增强了NK 1 -5-HT 1A受体的免疫共沉淀沿着去色素应答。SP和WAY 100635的协同作用引发了信号级联（细胞外调节的蛋白激酶p-JNK信号通路）的激活和p70 S6 K1磷酸化的抑制，并大大减少了体外和体内小鼠和斑马鱼的黑色素产生。此外，在5-htr 1aa +/−斑马鱼胚胎中没有发生SP诱导的脱色反应。总之，我们的系统性研究结果增加了我们对NK 1 R和5-HT 1AR在黑色素生成中作用的了解，并为治疗皮肤色素沉着不足/过度提供了可能的新治疗策略。吴，H.，赵玉，黄，Q，Cai，M.，Pan，Q.，傅，M.，安，X.，夏，Z.，刘，M.，Jin，Y.，他，L.，Shang，J. NK 1 R/5-HT 1AR相互作用与黑素生成的调节有关。FASEB J. 32，3193-3214（2018）。www.fasebj.org
Substance P (SP) is a candidate mediator along the brain–skin axis and can mimic the effects of stress to regulate melanogenesis. Previously, we and others have found that the regulation of SP for pigmentary function was mediated by neurokinin 1 receptor (NK1R). Emerging evidence has accumulated that psychologic stress can induce dysfunction in the cutaneous serotonin 5‐hydroxytryptamine (5‐HT)‐5‐HT1A/1B receptor system, thereby resulting in skin hypopigmentation. Moreover, NK1R and 5‐HTR (except 5‐HT3) belong to GPCR. The present study aimed at assessing the possible existence of NK1R‐5‐HTR interactions and related melanogenic functions. Western blot and PCR detection revealed that SP reduced expression of 5‐HT1A receptorviathe NK1 receptor. Biochemical analyses showed that NK1R and 5‐HT1AR could colocalize and interact in a cell and in the skin. When the N terminus of the NK1R protein was removed NK1R surface targeting was prevented, the interaction between NK1R‐5‐HT1AR decreased, and the depigmentation caused by SP and WAY100635 could be rescued. Importantly, pharmaceutical coadministration of NK1R agonist (SP) and 5‐HT1A antagonist (WAY100635) enhanced the NK1–5‐HT1A receptor coimmunoprecipitation along with the depigmentary response. SP and WAY100635 cooperation elicited activation of a signaling cascade (the extracellular, regulated protein kinase p‐JNK signaling pathway) and inhibition of p70S6K1 phosphorylation and greatly reduced melanin productionin vitroandin vivoin mice and zebrafish. Moreover, the SP‐induced depigmentation response did not be occur in 5‐htr1aa+/−zebrafish embryos. Taken together, the results of our systemic study increases our knowledge of the roles of NK1R and 5‐HT1AR in mela‐nogenesis and provides possible, novel therapeutic strategies for treatment of skin hypo/hyperpigmentation.—Wu, H., Zhao, Y., Huang, Q., Cai, M., Pan, Q., Fu, M., An, X., Xia, Z., Liu, M., Jin, Y., He, L., Shang, J. NK1R/5‐HT1AR interaction is related to the regulation of melanogenesis. FASEB J. 32, 3193–3214 (2018). www.fasebj.org