The human gonadotropin-inhibitory hormone ortholog RFamide-related peptide-3 suppresses gonadotropin-induced progesterone production in human granulosa cells

Hajime Oishi, Christian Klausen, George E. Bentley, Tomohiro Osugi, Kazuyoshi Tsutsui, C. Blake Gilks, Tetsu Yano, Peter C K Leung

    研究成果: Article

    42 引用 (Scopus)

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    RFamide-related peptide-3 (RFRP-3), a mammalian ortholog of avian gonadotropin-inhibitory hormone, has pronounced inhibitory effects on reproduction in a number of species. RFRP-3 suppresses gonadotropin release at the hypothalamic and/or pituitary levels; however, increasing evidence also suggests putative functions within the ovary. We have now demonstrated the expression of both RFRPand its receptor (GPR147) in primary cultures of human granulos a-lute in cells. Immunohistochemical analysis of normal human ovaries from premenopausal women showed that RFRPs and GPR147 were primarily localized in the granulosa cell layer of large preovulatory follicles as well as in the corpus luteum. Treatment of human granulosa-lutein cells with RFRP-3 reduced FSH-, LH- and forskolin-stimulated progesterone production and steroidogenic acute regulatory protein expression but did not affect basal or 8-bromoadenosine 3′5′-cyclic monophosphate stimulated levels. In addition, RFRP-3 inhibited gonadotropin- and forskolin-induced intracellular cAMP accumulation, and these effects were abolished by pretreatment with an inhibitor of inhibitory Gi/o proteins (pertussis toxin). Importantly, the effects of RFRP-3 on FSH-, LH-, and forskolin-induced cAMP and progesterone accumulation were completely eliminated by cotreatment with the bifunctional GPR147/GPR74 antagonist RF9 or by pretreatment with GPR147 small interfering RNA. These results suggest that RFRP-3 is expressed in human granulos a cells in which it acts via its receptor, GPR147, to inhibit gonadotropin signaling at the level of adenylyl cyclase via activation of a pertussis toxin-sensitive Gαi/o protein. This leads to reduced gonadotropin-stimulated cAMP accumulation and progesteronesynthesis, likely via reduced steroidogenic acute regulatory protein expression. Thus, ovarian RFRP-3/GPR147 signaling could contribute to normal ovarian function.

    元の言語English
    ページ(範囲)3435-3445
    ページ数11
    ジャーナルEndocrinology
    153
    発行部数7
    DOI
    出版物ステータスPublished - 2012 7

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    Granulosa Cells
    Gonadotropins
    Progesterone
    Hormones
    Colforsin
    Pertussis Toxin
    Ovary
    Luteal Cells
    Corpus Luteum
    RFamide peptide
    Adenylyl Cyclases
    Small Interfering RNA
    Reproduction
    Proteins

    ASJC Scopus subject areas

    • Endocrinology

    これを引用

    The human gonadotropin-inhibitory hormone ortholog RFamide-related peptide-3 suppresses gonadotropin-induced progesterone production in human granulosa cells. / Oishi, Hajime; Klausen, Christian; Bentley, George E.; Osugi, Tomohiro; Tsutsui, Kazuyoshi; Gilks, C. Blake; Yano, Tetsu; Leung, Peter C K.

    :: Endocrinology, 巻 153, 番号 7, 07.2012, p. 3435-3445.

    研究成果: Article

    Oishi, Hajime ; Klausen, Christian ; Bentley, George E. ; Osugi, Tomohiro ; Tsutsui, Kazuyoshi ; Gilks, C. Blake ; Yano, Tetsu ; Leung, Peter C K. / The human gonadotropin-inhibitory hormone ortholog RFamide-related peptide-3 suppresses gonadotropin-induced progesterone production in human granulosa cells. :: Endocrinology. 2012 ; 巻 153, 番号 7. pp. 3435-3445.
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    abstract = "RFamide-related peptide-3 (RFRP-3), a mammalian ortholog of avian gonadotropin-inhibitory hormone, has pronounced inhibitory effects on reproduction in a number of species. RFRP-3 suppresses gonadotropin release at the hypothalamic and/or pituitary levels; however, increasing evidence also suggests putative functions within the ovary. We have now demonstrated the expression of both RFRPand its receptor (GPR147) in primary cultures of human granulos a-lute in cells. Immunohistochemical analysis of normal human ovaries from premenopausal women showed that RFRPs and GPR147 were primarily localized in the granulosa cell layer of large preovulatory follicles as well as in the corpus luteum. Treatment of human granulosa-lutein cells with RFRP-3 reduced FSH-, LH- and forskolin-stimulated progesterone production and steroidogenic acute regulatory protein expression but did not affect basal or 8-bromoadenosine 3′5′-cyclic monophosphate stimulated levels. In addition, RFRP-3 inhibited gonadotropin- and forskolin-induced intracellular cAMP accumulation, and these effects were abolished by pretreatment with an inhibitor of inhibitory Gi/o proteins (pertussis toxin). Importantly, the effects of RFRP-3 on FSH-, LH-, and forskolin-induced cAMP and progesterone accumulation were completely eliminated by cotreatment with the bifunctional GPR147/GPR74 antagonist RF9 or by pretreatment with GPR147 small interfering RNA. These results suggest that RFRP-3 is expressed in human granulos a cells in which it acts via its receptor, GPR147, to inhibit gonadotropin signaling at the level of adenylyl cyclase via activation of a pertussis toxin-sensitive Gαi/o protein. This leads to reduced gonadotropin-stimulated cAMP accumulation and progesteronesynthesis, likely via reduced steroidogenic acute regulatory protein expression. Thus, ovarian RFRP-3/GPR147 signaling could contribute to normal ovarian function.",
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    AU - Oishi, Hajime

    AU - Klausen, Christian

    AU - Bentley, George E.

    AU - Osugi, Tomohiro

    AU - Tsutsui, Kazuyoshi

    AU - Gilks, C. Blake

    AU - Yano, Tetsu

    AU - Leung, Peter C K

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