Kisspeptin Signaling Is Indispensable for Neurokinin B, but not Glutamate, Stimulation of Gonadotropin Secretion in Mice

Kisspeptins (Kp), products of the Kiss1 gene that act via Gpr54 to potently stimulate GnRH secretion, operate as mediators of other regulatory signals of the gonadotropic axis. Mouse models of Gpr54 and/or Kiss1 inactivation have been used to address the contribution of Kp in the central control of...

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Published in:Endocrinology (Philadelphia) 2012-01, Vol.153 (1), p.316-328
Main Authors: García-Galiano, David, van Ingen Schenau, Dorette, Leon, Silvia, Krajnc-Franken, Magda A. M, Manfredi-Lozano, Maria, Romero-Ruiz, Antonio, Navarro, Victor M, Gaytan, Francisco, van Noort, Paula I, Pinilla, Leonor, Blomenröhr, Marion, Tena-Sempere, Manuel
Format: Article
Language:English
Subjects:
Adamantane - analogs & derivatives
Adamantane - pharmacology
Animals
Biological and medical sciences
Dipeptides - pharmacology
Follicle Stimulating Hormone - secretion
Fundamental and applied biological sciences. Psychology
Galanin-Like Peptide - pharmacology
Galanin-Like Peptide - physiology
Glutamic Acid - physiology
Gonadotropin-Releasing Hormone - secretion
Gonadotropins - secretion
Hypogonadism - genetics
Hypogonadism - pathology
Hypogonadism - physiopathology
Kisspeptins - physiology
Luteinizing Hormone - secretion
Male
Mice
Mice, Knockout
Models, Neurological
Naltrexone - analogs & derivatives
Naltrexone - pharmacology
Neurokinin B - agonists
Neurokinin B - physiology
Peptide Fragments - pharmacology
Receptors, G-Protein-Coupled - deficiency
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - physiology
Receptors, Kisspeptin-1
Receptors, N-Methyl-D-Aspartate - agonists
Receptors, N-Methyl-D-Aspartate - physiology
Receptors, Neuropeptide - antagonists & inhibitors
Signal Transduction - physiology
Substance P - analogs & derivatives
Substance P - pharmacology
Testosterone - physiology
Vertebrates: endocrinology
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Summary:Kisspeptins (Kp), products of the Kiss1 gene that act via Gpr54 to potently stimulate GnRH secretion, operate as mediators of other regulatory signals of the gonadotropic axis. Mouse models of Gpr54 and/or Kiss1 inactivation have been used to address the contribution of Kp in the central control of gonadotropin secretion; yet, phenotypic and hormonal differences have been detected among the transgenic lines available. We report here a series of neuroendocrine analyses in male mice of a novel Gpr54 knockout (KO) model, generated by heterozygous crossing of a loxP-Gpr54/Protamine-Cre double mutant line. Gpr54-null males showed severe hypogonadotropic hypogonadism but retained robust responsiveness to GnRH. Gonadotropic responses to the agonist of ionotropic glutamate receptors, N-methyl-d-aspartate, were attenuated, but persisted, in Gpr54-null mice. In contrast, LH secretion after activation of metabotropic glutamate receptors was totally preserved in the absence of Gpr54 signaling. Detectable, albeit reduced, LH responses were also observed in Gpr54 KO mice after intracerebroventricular administration of galanin-like peptide or RF9, putative antagonist of neuropeptide FF receptors for the mammalian ortholog of gonadotropin-inhibiting hormone. In contrast, the stimulatory effect of senktide, agonist of neurokinin B (NKB; cotransmitter of Kiss1 neurons), was totally abrogated in Gpr54 KO males. Lack of Kp signaling also eliminated feedback LH responses to testosterone withdrawal. However, residual but sustained increases of FSH were detected in gonadectomized Gpr54 KO males, in which testosterone replacement failed to fully suppress circulating FSH levels. In sum, our study provides novel evidence for the relative importance of Kp-dependent vs. -independent actions of several key regulators of GnRH secretion, such as glutamate, galanin-like peptide, and testosterone. In addition, our data document for the first time the indispensable role of Kp signaling in mediating the stimulatory effects of NKB on LH secretion, thus supporting the hypothesis that NKB actions on GnRH neurons are indirectly mediated via its ability to regulate Kiss1 neuronal output.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2011-1260