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Endocrinology Vol. 146, No. 1 156-163
Copyright © 2005 by The Endocrine Society

Characterization of the Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide, the Natural Ligand of GPR54

V. M. Navarro1, J. M. Castellano1, R. Fernández-Fernández, S. Tovar, J. Roa, A. Mayen, R. Nogueiras, M. J. Vazquez, M. L. Barreiro, P. Magni, E. Aguilar, C. Dieguez, L. Pinilla and M. Tena-Sempere

Department of Cell Biology, Physiology and Immunology (V.M.N., J.M.C., R.F.-F., J.R., A.M., M.L.B., E.A., L.P., M.T.-S.), University of Córdoba, 14004 Córdoba, Spain; Institute of Endocrinology (P.M.), University of Milan, 20133 Milan, Italy; and Department of Physiology (S.T., R.N., M.J.V., C.D.), University of Santiago de Compostela, 15705 Santiago de Compostela, Spain

Address all correspondence and requests for reprints to: Manuel Tena-Sempere, Physiology Section, Department of Cell Biology, Physiology, and Immunology, Faculty of Medicine, University of Córdoba, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain. E-mail: fi1tesem{at}uco.es.

Loss-of-function mutations of the gene encoding GPR54, the putative receptor for the KiSS-1-derived peptide metastin, have been recently associated with hypogonadotropic hypogonadism, in both rodents and humans. Yet the actual role of the KiSS-1/GPR54 system in the neuroendocrine control of gonadotropin secretion remains largely unexplored. To initiate such analysis, the effects of KiSS-1 peptide on LH secretion were monitored using in vivo and in vitro settings under different experimental conditions. Central intracerebroventricular administration of KiSS-1 peptide potently elicited LH secretion in vivo over a range of doses from 10 pmol to 1 nmol. The effect of centrally injected KiSS-1 appeared to be mediated via the hypothalamic LHRH. However, no effect of central administration of KiSS-1 was detected on relative LHRH mRNA levels. Likewise, systemic (ip and iv) injection of KiSS-1 markedly stimulated LH secretion. This effect was similar in terms of maximum response to that of central administration of KiSS-1 and might be partially attributed to its ability to stimulate LH secretion directly at the pituitary. Finally, the LH-releasing activity of KiSS-1 was persistently observed after blockade of endogenous excitatory amino acid and nitric oxide pathways, i.e. relevant neurotransmitters in the neuroendocrine control of LH secretion. In summary, our results provide solid evidence for a potent stimulatory effect of KiSS-1 on LH release, acting at central levels (likely the hypothalamus) and eventually at the pituitary, and further document a novel role of the KiSS-1/GPR54 system as a relevant downstream element in the neuroendocrine network governing LH secretion.




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J. T. Smith, H. M. Dungan, E. A. Stoll, M. L. Gottsch, R. E. Braun, S. M. Eacker, D. K Clifton, and R. A. Steiner
Differential Regulation of KiSS-1 mRNA Expression by Sex Steroids in the Brain of the Male Mouse
Endocrinology, July 1, 2005; 146(7): 2976 - 2984.
[Abstract] [Full Text] [PDF]

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S. B. Seminara and U. B. Kaiser
New Gatekeepers of Reproduction: GPR54 and Its Cognate Ligand, KiSS-1
Endocrinology, April 1, 2005; 146(4): 1686 - 1688.
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V. M. Navarro, J. M. Castellano, R. Fernandez-Fernandez, S. Tovar, J. Roa, A. Mayen, M. L. Barreiro, F. F. Casanueva, E. Aguilar, C. Dieguez, et al.
Effects of KiSS-1 Peptide, the Natural Ligand of GPR54, on Follicle-Stimulating Hormone Secretion in the Rat
Endocrinology, April 1, 2005; 146(4): 1689 - 1697.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
M. Shahab, C. Mastronardi, S. B. Seminara, W. F. Crowley, S. R. Ojeda, and T. M. Plant
Increased hypothalamic GPR54 signaling: A potential mechanism for initiation of puberty in primates
PNAS, February 8, 2005; 102(6): 2129 - 2134.
[Abstract] [Full Text] [PDF]


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