Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells

May 25, 2013Molecular and cellular endocrinology

Melatonin receptor activation reduces stress hormone production through BMP-4 in pituitary cells

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Abstract

Melatonin and ramelteon suppressed CRH-induced ACTH production in mouse corticotrope cells.

Both melatonin and ramelteon inhibited ACTH production and proopiomelanocortin (POMC) transcription.
Ramelteon was more effective than melatonin in reducing basal and CRH-induced levels of POMC mRNA and ACTH.
Co-treatment with BMP-4 enhanced the inhibitory effects of melatonin and ramelteon on ACTH production.
BMP-4 stimulation increased the expression of melatonin type-1 receptors (MT1R).
Inhibition of AKT signaling reversed the effects of MT1R on POMC transcription and BMP-4-induced Id-1 transcription.
MT1R signaling and BMP-4 actions appeared to enhance each other, influencing ACTH production.

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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.

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Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells

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