A novel interaction of kisspeptin, estrogen and BMP-4 in GnRH regulation by GT1-7 cells

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 134-163-GnRH & Gonadotroph Biology & Signaling
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-143
Tomohiro Terasaka*1, Fumio Otsuka1, Naoko Tsukamoto2, Kishio Toma2, Eri Nakamura2, Tomoko Miyoshi1, Kenichi Inagaki2, Mark A Lawson3 and Hirofumi Makino1
1Okayama Univ Grad School, Okayama, Japan, 2Okayama University Hospital, Okayama, Japan, 3Univ of California-San Diego, La Jolla, CA
Reproduction is integrated by interaction of neural and hormonal signals converging on hypothalamic neurons for controlling gonadotropin-releasing hormone (GnRH).  Recently, an understanding of the physiological control of the reproductive axis has been advanced by identification of the essential role of kisspeptin.  Kisspeptin, the peptide product of the kiss1 gene and the endogenous agonist for the GRP54 receptor, plays a key role in the regulation of GnRH secretion.  In the present study, we studied the interaction between kisspeptin, estrogen and BMPs in the regulation of GnRH production by using mouse hypothalamic GT1-7 cells.  It was revealed that GT1-7 cells express GnRH, Kiss1, GPR54, ERa and ERb.  Treatment with kisspeptin increased GnRH mRNA expression and GnRH protein production in a concentration-dependent manner.  The expression levels of kiss1 and GPR54 were not changed by kisspeptin stimulation.  Effects of kisspeptin on GnRH induction were suppressed by co-treatment with BMPs, with BMP-4 action being the most potent for suppressing kisspeptin effects on GnRH expression.  On the other hand, the expression of a kisspeptin receptor, GPR54, was potently suppressed by BMPs, and the suppressive effects of BMPs on GPR54 expression were reversed in the presence of kisspeptin.  It was also revealed that the BMP-receptor signaling detected by Smad1/5/8 phosphorylation and Id-1 expression was suppressed by kisspeptin-induced upregulation of inhibitory Smad6/7.  In addition to the estrogen action on GnRH suppression as a negative feedback, estrogen upregulated GPR54 expression, while kisspeptin increased the expression levels of ERa and ERb, suggesting that the actions of estrogen and kisspeptin are mutually enhanced in GT1-7 cells.  Moreover, kisspeptin stimulates MAPKs and AKT signaling, particularly in the presence of estrogen, in which the ERK signaling was functionally involved in the kisspeptin-induced GnRH expression.  BMP-4 was found to suppress kisspeptin-stimulated GnRH expression by reducing ERK signaling activity.  Collectively, the axis of kisspeptin-induced GnRH production is bi-directionally controlled, being augmented by an interaction between ER and GPR54 and being suppressed by BMP-4 action.  These results suggest the importance of balanced activities between ER-GPR54 and BMP-4 signaling for performing a healthy GnRH secretory profile in the reproduction system.  This novel interaction of kisspeptin, estrogen and BMP-4 may be a key for fine-tuning of GnRH regulation under the dynamic influence of estrogen level.

Nothing to Disclose: TT, FO, NT, KT, EN, TM, KI, MAL, HM

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