Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1-9 |
| Number of pages | 9 |
| Journal | Molecular and Cellular Endocrinology |
| Volume | 375 |
| Issue number | 1-2 |
| DOIs | |
| Publication status | Published - Aug 5 2013 |
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Keywords
- Adrenocorticotropin
- Bone morphogenetic protein
- Corticotrope
- Corticotropin-releasing hormone
- Melatonin and ramelteon
ASJC Scopus subject areas
- Endocrinology
- Molecular Biology
- Biochemistry
Cite this
Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells. / Tsukamoto, Naoko; Otsuka, Fumio; Ogura-Ochi, Kanako; Inagaki, Kenichi; Nakamura, Eri; Toma, Kishio; Terasaka, Tomohiro; Iwasaki, Yasumasa; Makino, Hirofumi.
In: Molecular and Cellular Endocrinology, Vol. 375, No. 1-2, 05.08.2013, p. 1-9.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells
AU - Tsukamoto, Naoko
AU - Otsuka, Fumio
AU - Ogura-Ochi, Kanako
AU - Inagaki, Kenichi
AU - Nakamura, Eri
AU - Toma, Kishio
AU - Terasaka, Tomohiro
AU - Iwasaki, Yasumasa
AU - Makino, Hirofumi
PY - 2013/8/5
Y1 - 2013/8/5
N2 - 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.
AB - 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.
KW - Adrenocorticotropin
KW - Bone morphogenetic protein
KW - Corticotrope
KW - Corticotropin-releasing hormone
KW - Melatonin and ramelteon
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UR - http://www.scopus.com/inward/citedby.url?scp=84878700225&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2013.05.010
DO - 10.1016/j.mce.2013.05.010
M3 - Article
C2 - 23701823
AN - SCOPUS:84878700225
VL - 375
SP - 1
EP - 9
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
IS - 1-2
ER -