title: Kisspeptin signaling is indispensable for neurokinin B, but not glutamate, stimulation of gonadotropin secretion in mice.
abstract: 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.
authors: Department of Cell Biology, Physiology and Immunology, University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain.
authors: David
authors: D
authors: García-Galiano
authors: Dorette
authors: D
authors: van Ingen Schenau
authors: Silvia
authors: S
authors: Leon
authors: Magda A M
authors: MA
authors: Krajnc-Franken
authors: Maria
authors: M
authors: Manfredi-Lozano
authors: Antonio
authors: A
authors: Romero-Ruiz
authors: Victor M
authors: VM
authors: Navarro
authors: Francisco
authors: F
authors: Gaytan
authors: Paula I
authors: PI
authors: van Noort
authors: Leonor
authors: L
authors: Pinilla
authors: Marion
authors: M
authors: Blomenröhr
authors: Manuel
authors: M
authors: Tena-Sempere
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D044089:Galanin-Like Peptide / Q000494:pharmacology / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006062:Gonadotropins / Q000378:metabolism*; D007006:Hypogonadism / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D059648:Kisspeptins / Q000502:physiology*; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D015287:Neurokinin B / Q000819:agonists / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000074502:Receptors, Kisspeptin-1; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000502:physiology; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D013739:Testosterone / Q000502:physiology
chemical_list: D004151:Dipeptides; D044089:Galanin-Like Peptide; D006062:Gonadotropins; C491406:Kiss1 protein, rat; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D016194:Receptors, N-Methyl-D-Aspartate; D018013:Receptors, Neuropeptide; C508361:adamantylcarbonyl-arginyl-phenylalaninamide; C083929:neuropeptide FF receptor; C054724:senktide; D013373:Substance P; D007987:Gonadotropin-Releasing Hormone; C051844:norbinaltorphimine; D018698:Glutamic Acid; D013739:Testosterone; D009271:Naltrexone; D015287:Neurokinin B; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D000218:Adamantane