Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis

Takayoshi Ubuka, Kevin Morgan, Adam J. Pawson, Tomohiro Osugi, Vishwajit S. Chowdhury, Hiroyuki Minakata, Kazuyoshi Tsutsui, Robert P. Millar, George E. Bentley

    Research output: Contribution to journalArticle

    168 Citations (Scopus)

    Abstract

    The existence of a hypothalamic gonadotropin-inhibiting system has been elusive. A neuropeptide named gonadotropin- inhibitory hormone (GnIH, SIKPSAYLPLRF-NH2) which directly inhibits gonadotropin synthesis and release from the pituitary was recently identified in quail hypothalamus. Here we identify GnIH homologs in the human hypothalamus and characterize their distribution and biological activity. GnIH homologs were isolated from the human hypothalamus by immunoaffinity purification, and then identified as MPHSFANLPLRF-NH2 (human RFRP-1) and VPNLPQRF-NH2 (human RFRP-3) by mass spectrometry. Immunocytochemistry revealed GnIH-immunoreactive neuronal cell bodies in the dorsomedial region of the hypothalamus with axonal projections to GnRH neurons in the preoptic area as well as to the median eminence. RT-PCR and subsequent DNA sequencing of the PCR products identified human GnIH receptor (GPR147) mRNA expression in the hypothalamus as well as in the pituitary. In situ hybridization further identified the expression of GPR147 mRNA in luteinizing hormone producing cells (gonadotropes). Human RFRP-3 has recently been shown to be a potent inhibitor of gonadotropin secretion in cultured sheep pituitary cells by inhibiting Ca2+ mobilization. It also directly modulates GnRH neuron firing. The identification of two forms of GnIH (RFRP-1 and RFRP-3) in the human hypothalamus which targets human GnRH neurons and gonadotropes and potently inhibit gonadotropin in sheep models provides a new paradigm for the regulation of hypothalamic-pituitary-gonadal axis in man and a novel means for manipulating reproductive functions.

    Original languageEnglish
    Article numbere8400
    JournalPLoS One
    Volume4
    Issue number12
    DOIs
    Publication statusPublished - 2009

    Fingerprint

    Forensic Anthropology
    Gonadotropins
    Gonadotropin-Releasing Hormone
    hypothalamus
    Hypothalamus
    Neurons
    receptors
    gonadotropins
    neurons
    Messenger RNA
    Luteinizing Hormone
    Bioactivity
    Neuropeptides
    Purification
    Mass spectrometry
    Sheep
    Cells
    Hormones
    hypothalamic regulation
    Polymerase Chain Reaction

    ASJC Scopus subject areas

    • Agricultural and Biological Sciences(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Medicine(all)

    Cite this

    Ubuka, T., Morgan, K., Pawson, A. J., Osugi, T., Chowdhury, V. S., Minakata, H., ... Bentley, G. E. (2009). Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. PLoS One, 4(12), [e8400]. https://doi.org/10.1371/journal.pone.0008400

    Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. / Ubuka, Takayoshi; Morgan, Kevin; Pawson, Adam J.; Osugi, Tomohiro; Chowdhury, Vishwajit S.; Minakata, Hiroyuki; Tsutsui, Kazuyoshi; Millar, Robert P.; Bentley, George E.

    In: PLoS One, Vol. 4, No. 12, e8400, 2009.

    Research output: Contribution to journalArticle

    Ubuka, T, Morgan, K, Pawson, AJ, Osugi, T, Chowdhury, VS, Minakata, H, Tsutsui, K, Millar, RP & Bentley, GE 2009, 'Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis', PLoS One, vol. 4, no. 12, e8400. https://doi.org/10.1371/journal.pone.0008400
    Ubuka, Takayoshi ; Morgan, Kevin ; Pawson, Adam J. ; Osugi, Tomohiro ; Chowdhury, Vishwajit S. ; Minakata, Hiroyuki ; Tsutsui, Kazuyoshi ; Millar, Robert P. ; Bentley, George E. / Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. In: PLoS One. 2009 ; Vol. 4, No. 12.
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