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

Naoko Tsukamoto, Fumio Otsuka, Kanako Ogura-Ochi, Kenichi Inagaki, Eri Nakamura, Kishio Toma, Tomohiro Terasaka, Yasumasa Iwasaki, Hirofumi Makino

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 languageEnglish
Pages (from-to)1-9
Number of pages9
JournalMolecular and Cellular Endocrinology
Volume375
Issue number1-2
DOIs
Publication statusPublished - Aug 5 2013

Fingerprint

Bone Morphogenetic Protein 4
Melatonin Receptors
Melatonin
Adrenocorticotropic Hormone
Corticotropin-Releasing Hormone
Pro-Opiomelanocortin
Chemical activation
Transcription
Bone Morphogenetic Protein Receptors
MAP Kinase Signaling System
Hand Bones
Bone Morphogenetic Proteins
Phosphorylation
Circadian Rhythm
Bioactivity
ramelteon
Tuning
Genes
Messenger RNA

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 journalArticle

@article{6cc817fbce76406b8254b286274547b9,
title = "Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells",
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.",
keywords = "Adrenocorticotropin, Bone morphogenetic protein, Corticotrope, Corticotropin-releasing hormone, Melatonin and ramelteon",
author = "Naoko Tsukamoto and Fumio Otsuka and Kanako Ogura-Ochi and Kenichi Inagaki and Eri Nakamura and Kishio Toma and Tomohiro Terasaka and Yasumasa Iwasaki and Hirofumi Makino",
year = "2013",
month = "8",
day = "5",
doi = "10.1016/j.mce.2013.05.010",
language = "English",
volume = "375",
pages = "1--9",
journal = "Molecular and Cellular Endocrinology",
issn = "0303-7207",
publisher = "Elsevier Ireland Ltd",
number = "1-2",

}

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

UR - http://www.scopus.com/inward/record.url?scp=84878700225&partnerID=8YFLogxK

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

VL - 375

SP - 1

EP - 9

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

SN - 0303-7207

IS - 1-2

ER -