Activation of the Melatonin Receptor MT1 by the Natural Product Gastrodin to Promote Sleep

IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Lijing Zhang, Mengli Lan, Hui Chen, Richard Ward, Ya Zhao, Jing Guo, Lang Xiong, Xiuyu Yang, Yuxuan Pu, Cheng Xiang, Su An, Xiaoxi Guo, Tian-Rui Xu, Yang Yang
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Abstract

The activation of melatonin receptors, belonging to the G-protein coupled receptors (GPCRs) superfamily, has been recognized as a vital approach in the clinical management of sleep disorders. Although the natural agonist melatonin and synthetic agonists (e.g., ramelteon) targeting these receptors have been extensively studied, the identification of natural compounds acting as ligands remains elusive. We applied a combination of methods including GPCR-induced ERK1/2 MAP kinase phosphorylation assay, inhibition of forskolin-stimulated cAMP production, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), solvent-induced protein precipitation (SIP), 2-[125I]-iodomelatonin binding assay, fluorescence resonance energy transfer (FRET), and molecular docking to investigate MT1 activation by gastrodin and the gastrodin–MT1 interaction. The in vivo study was performed with mice whose MT1 receptors were knocked down in the suprachiasmatic nucleus (SCN) of the brain. The sleep behavior and sleep-related hypothalamic neurotransmitters were evaluated. The results identified that the gastrodin acted as an agonist of MT1 through direct binding to the receptor. The interaction of gastrodin-MT1 was similar to that of melatonin–MT1. The in vivo sleep-promoting effect of the gastrodin depended on the presence of MT1 in the SCN and was associated with the hypothalamic neurotransmitters, similarly to melatonin.

褪黑素受体属于 G 蛋白偶联受体(GPCRs)超家族,激活褪黑素受体已被认为是临床治疗睡眠障碍的重要方法。尽管针对这些受体的天然激动剂褪黑素和合成激动剂(如雷美替胺)已被广泛研究,但作为配体的天然化合物的鉴定仍然难以确定。我们采用了多种方法,包括 GPCR 诱导的 ERK1/2 MAP 激酶磷酸化试验、抑制福斯可林刺激的 cAMP 生成、药物亲和力反应靶标稳定性(DARTS)、细胞热转移试验(CETSA)、通过溶剂诱导蛋白沉淀(SIP)、2-[125I]-碘美拉宁结合试验、荧光共振能量转移(FRET)和分子对接来研究胃泌素对 MT1 的激活作用以及胃泌素与 MT1 之间的相互作用。体内研究是在大脑嗜上核(SCN)的MT1受体被敲除的小鼠身上进行的。对小鼠的睡眠行为和与睡眠相关的下丘脑神经递质进行了评估。结果发现,天麻素通过与受体直接结合而成为MT1的激动剂。天麻素-MT1的相互作用与褪黑素-MT1的相互作用相似。天麻素的体内促进睡眠作用取决于MT1在SCN中的存在,并与下丘脑神经递质有关,与褪黑素类似。
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来源期刊
Journal of Pineal Research
Journal of Pineal Research 医学-内分泌学与代谢
CiteScore
17.70
自引率
4.90%
发文量
66
审稿时长
1 months
期刊介绍: The Journal of Pineal Research welcomes original scientific research on the pineal gland and melatonin in vertebrates, as well as the biological functions of melatonin in non-vertebrates, plants, and microorganisms. Criteria for publication include scientific importance, novelty, timeliness, and clarity of presentation. The journal considers experimental data that challenge current thinking and welcomes case reports contributing to understanding the pineal gland and melatonin research. Its aim is to serve researchers in all disciplines related to the pineal gland and melatonin.
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