Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells.
Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells.
复制标题
褪黑素受体激活可通过垂体 AtT20 细胞通过 BMP-4 作用抑制促肾上腺皮质激素的产生。
DOI：
10.1016/j.mce.2013.05.010
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Makino H.
中科院分区：
文献类型：
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作者：
Tsukamoto N;Otsuka F;Ogura-Ochi K;Inagaki K;Nakamura E;Toma K;Terasaka T;Iwasaki Y;Makino H.
褪黑激素是昼夜节律的调节者，其在促肾上腺皮质激素(ACTH)分泌中的作用尚未阐明。在这项研究中，我们利用表达褪黑素1型(MT1R)而不表达2型(MT2R)受体的小鼠促肾上腺皮质激素ATT20细胞，研究了褪黑素对ACTH产生的影响与骨形态发生蛋白-4(BMP-4)生物学活性的关系。我们先前报道BMP-4通过抑制MAPK信号通路抑制促肾上腺皮质激素释放激素(CRH)诱导的ACTH的产生和前阿片黑素皮质素(POMC)的转录。褪黑素和MT1R/MT2R激动剂Ramelteon均可抑制CRH诱导的ACTH生成、POMC转录和cAMP合成。Ramelteon对基础和CRH诱导的POMC mRNA和ACTH水平的抑制作用强于褪黑素。褪黑素或Ramelteon与BMP-4联合治疗可显著抑制CRH诱导的ACTH的产生。值得注意的是，BMP-4刺激可上调MT1R的表达水平。褪黑素和Ramelteon对CRH诱导的POMC转录和cAMP合成的抑制作用不受MT2R拮抗剂Luzindole的影响。另一方面，在褪黑激素和Ramelteon的存在下，BMP-4诱导的Smad1/5/8磷酸化和BMP靶基因ID-1的表达增强。考虑到Ramelteon上调BMP受体ALK-3/BMPRII的表达水平，MT1R作用可能在BMP受体信号转导中起促进作用。在包括AKT、ERK和JNK在内的MT1R信号通路中，抑制AKT信号通路可有效逆转MT1R对CRH诱导的POMC转录和BMP-4诱导的ID-1转录的影响。总的来说，MT1R信号和BMP-4的作用相互增强，导致促肾上腺皮质激素细胞产生ACTH的微调。
The role of melatonin, a regulator of circadian rhythm, in adrenocorticotropin (ACTH) production by corticotrope cells has not been elucidated. In this study, we investigated the effect of melatonin on ACTH production in relation to the biological activity of bone morphogenetic protein (BMP)-4 using mouse corticotrope AtT20 cells that express melatonin type-1 (MT1R) but not type-2 (MT2R) receptors. We previously reported that BMP-4 inhibits corticotropin-releasing hormone (CRH)-induced ACTH production and proopiomelanocortin (POMC) transcription by inhibiting MAPK signaling. Both melatonin and an MT1R/MT2R agonist, ramelteon, suppressed CRH-induced ACTH production, POMC transcription and cAMP synthesis. The inhibitory effects of ramelteon on basal and CRH-induced POMC mRNA and ACTH levels were more potent than those of melatonin. Treatment with melatonin or ramelteon in combination with BMP-4 additively suppressed CRH-induced ACTH production. Of note, the level of MT1R expression was upregulated by BMP-4 stimulation. The suppressive effects of melatonin and ramelteon on POMC transcription and cAMP synthesis induced by CRH were not affected by an MT2R antagonist, luzindole. On the other hand, BMP-4-induced Smad1/5/8 phosphorylation and the expression of a BMP target gene, Id-1, were augmented in the presence of melatonin and ramelteon. Considering that the expression levels of BMP receptors, ALK-3/BMPRII, were increased by ramelteon, MT1R action may play an enhancing role in BMP-receptor signaling. Among the MT1R signaling pathways including AKT, ERK and JNK pathways, inhibition of AKT signaling functionally reversed the MT1R effects on both CRH-induced POMC transcription and BMP-4-induced Id-1 transcription. Collectively, MT1R signaling and BMP-4 actions were mutually augmented, leading to fine-tuning of ACTH production by corticotrope cells.