Inhibitory effects of melatonin on adrenocorticotropin production via BMP-4 activation by pituitary corticotrope cells

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 72-87-HPA Axis
Basic
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-75
Naoko Tsukamoto*1, Fumio Otsuka2, Kanako Ogura-Ochi1, Kenichi Inagaki1, Eri Nakamura1, Kishio Toma1, Tomohiro Terasaka2, Yasumasa Iwasaki3 and Hirofumi Makino2
1Okayama University Hospital, Okayama, Japan, 2Okayama Univ Grad School, Okayama, Japan, 3Health Service Center, Kochi, Japan
The role of melatonin, a regulator of circadian rhythm, in ACTH production by corticotrope cells has not been elucidated.  As for the interrelationship between melatonin secretion and the HPA axis, a specific change of melatonin secretion in situations of hypercortisolemia including ACTH-dependent and ACTH-independent Cushing’s syndrome has been reported.  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 (MT1) but not MT2 receptors.  We earlier reported that BMP-4 inhibits CRH-induced ACTH production and POMC transcription by inhibiting MAPK signaling.  Both melatonin and an MT1/MT2 receptor agonist, ramelteon, suppressed CRH-induced ACTH production, POMC transcription and cAMP synthesis, the inhibitory effect of ramelteon being more potent than that of melatonin.  Basal ACTH level and POMC transcription were suppressed by ramelteon but not by melatonin.  Treatment with melatonin or ramelteon in combination with BMP-4 additively suppressed basal, CRH- and GHRP-induced POMC transcription.  Of note, the level of MT1 receptor expression was upregulated by BMP-4 stimulation.  The suppressive effects of melatonin on POMC mRNA and cAMP synthesis induced by CRH were not affected by an MT2-receptor 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, MT1-receptor signaling may play a role in enhancing role of BMP-receptor signaling.  Stimulation by melatonin and ramelteon also activated AKT, ERK and JNK pathways, in which inhibition of AKT signaling functionally reversed the effects of MT1 on both CRH-induced POMC transcription and BMP-4-induced Id-1 transcription.  Thus, melatonin and BMP-4 activities were mutually augmented, leading to fine-tuning of ACTH production by corticotrope cells.  The use of MT1 activity and the correction of abnormal circadian rhythm may be a new clue for regulating ACTH and cortisol levels in cases of Cushing’s diseases when the control of disease activities are incomplete after pituitary surgery.  Administration of a selective MT1/MT2 receptor agonist is not only clinically effective for insomnia but may also be helpful for controlling ACTH production by corticotrope tumor cells.  A future clinical study is needed to determine the usefulness of melatonin action for suppressing Cushing’s disease.

Nothing to Disclose: NT, FO, KO, KI, EN, KT, TT, YI, HM

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