title: Mutual effects of melatonin and activin on induction of aldosterone production by human adrenocortical cells.
abstract: Melatonin has been reported to suppress adrenocorticotropin (ACTH) secretion in the anterior pituitary and cortisol production in the adrenal by different mechanisms. However, the effect of melatonin on aldosterone production has remained unknown. In this study, we investigated the role of melatonin in the regulation of aldosterone production using human adrenocortical H295R cells by focusing on the activin system expressed in the adrenal. Melatonin receptor MT1 mRNA and protein were expressed in H295R cells and the expression levels of MT1 were increased by activin treatment. Activin increased ACTH-induced, but not angiotensin II (Ang II)-induced, aldosterone production. Melatonin alone did not affect basal synthesis of either aldosterone or cortisol. However, melatonin effectively enhanced aldosterone production induced by co-treatment with ACTH and activin, although melatonin had no effect on aldosterone production induced by Ang II in combination with activin. These changes in steroidogenesis became apparent when the steroid production was evaluated by the ratio of aldosterone/cortisol. Melatonin also enhanced dibutyryl-AMP-induced aldosterone/cortisol levels in the presence of activin, suggesting a functional link to the cAMP-PKA pathway for induction of aldosterone production by melatonin and activin. In accordance with the data for steroids, ACTH-induced, but not Ang II-induced, cAMP synthesis was also amplified by co-treatment with melatonin and activin. Furthermore, the ratio of ACTH-induced mRNA level of CYP11B2 compared with that of CYP17 was amplified in the condition of treatment with both melatonin and activin. In addition, melatonin increased expression of the activin type-I receptor ALK-4 but suppressed expression of inhibitory Smads6/7, leading to the enhancement of Smad2 phosphorylation. Collectively, the results showed that melatonin facilitated aldosterone production induced by ACTH and activin via the cAMP-PKA pathway. The results also suggested that mutual enhancement of melatonin and activin receptor signaling is involved in the induction of aldosterone output by adrenocortical cells.
authors.affiliation: Department of Medicine and Clinical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan. Electronic address: fumiotsu@md.okayama-u.ac.jp.
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.affiliation: Department of Medicine and Clinical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsukamoto-Yamauchi
authors.affiliation: Department of Medicine and Clinical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.affiliation: Department of Medicine and Clinical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hosoya
authors.affiliation: Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Nakamura
authors.affiliation: Department of Medicine and Clinical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Terasaka
authors.affiliation: Department of Medicine and Clinical Science, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Motoshi
authors.initials: M
authors.lastname: Komatsubara
authors.affiliation: Okayama University Hospital, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D030201:Activin Receptors, Type I / Q000096:biosynthesis; D028341:Activins / Q000494:pharmacology*; D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism* / Q000494:pharmacology; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000378:metabolism; D045744:Cell Line, Tumor; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D008550:Melatonin / Q000494:pharmacology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D044122:Receptor, Melatonin, MT1 / Q000096:biosynthesis / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D051905:Smad6 Protein / Q000096:biosynthesis; D051906:Smad7 Protein / Q000096:biosynthesis; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D044122:Receptor, Melatonin, MT1; C497782:SMAD2 protein, human; C497802:SMAD6 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051905:Smad6 Protein; D051906:Smad7 Protein; D028341:Activins; D000804:Angiotensin II; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; C498932:ACVR1B protein, human; D030201:Activin Receptors, Type I; D008550:Melatonin; D006854:Hydrocortisone
keywords: Activin; Adrenocorticotropin; Aldosterone; Melatonin; Steroidogenesis