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.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsukamoto
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Kanako
authors.initials: K
authors.lastname: Ogura-Ochi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Eri
authors.initials: E
authors.lastname: Nakamura
authors.forename: Kishio
authors.initials: K
authors.lastname: Toma
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Terasaka
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis*; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology*; D002460:Cell Line; D052680:Corticotrophs / Q000378:metabolism*; D016895:Culture Media, Serum-Free; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007192:Indenes / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008550:Melatonin / Q000502:physiology; D051379:Mice; D010902:Pituitary Gland / Q000166:cytology; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044122:Receptor, Melatonin, MT1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D016895:Culture Media, Serum-Free; D007192:Indenes; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D051785:Smad Proteins; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; C495910:ramelteon; D048049:Extracellular Signal-Regulated MAP Kinases; D008550:Melatonin