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Endocrinology Vol. 145, No. 10 4565-4574
Copyright © 2004 by The Endocrine Society

Developmental and Hormonally Regulated Messenger Ribonucleic Acid Expression of KiSS-1 and Its Putative Receptor, GPR54, in Rat Hypothalamus and Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide

V. M. Navarro, J. M. Castellano, R. Fernández-Fernández, M. L. Barreiro, J. Roa, J. E. Sanchez-Criado, 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., M.L.B., J.R., J.E.S.-C., E.A., L.P., M.T.-S.), University of Cordoba, 14004 Cordoba, Spain; and Department of Physiology (C.D.), University of Santiago de Compostela, 15705 Santiago de Compostela, Spain

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

The gonadotropic axis is centrally controlled by a complex regulatory network of excitatory and inhibitory signals that is activated at puberty. Recently, loss of function mutations of the gene encoding G protein-coupled receptor 54 (GPR54), the putative receptor for the KiSS-1-derived peptide metastin, have been associated with lack of puberty onset and hypogonadotropic hypogonadism. Yet the pattern of expression and functional role of the KiSS-1/GPR54 system in the rat hypothalamus remain unexplored to date. In the present work, expression analyses of KiSS-1 and GPR54 genes were conducted in different physiological and experimental settings, and the effects of central administration of KiSS-1 peptide on LH release were assessed in vivo. Persistent expression of KiSS-1 and GPR54 mRNAs was detected in rat hypothalamus throughout postnatal development, with maximum expression levels at puberty in both male and female rats. Hypothalamic expression of KiSS-1 and GPR54 genes changed throughout the estrous cycle and was significantly increased after gonadectomy, a rise that was prevented by sex steroid replacement both in males and females. Moreover, hypothalamic expression of the KiSS-1 gene was sensitive to neonatal imprinting by estrogen. From a functional standpoint, intracerebroventricular administration of KiSS-1 peptide induced a dramatic increase in serum LH levels in prepubertal male and female rats as well as in adult animals. In conclusion, we provide novel evidence of the developmental and hormonally regulated expression of KiSS-1 and GPR54 mRNAs in rat hypothalamus and the ability of KiSS-1 peptide to potently stimulate LH secretion in vivo. Our current data support the contention that the hypothalamic KiSS-1/GPR54 system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood.




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Endocr. Rev.Home page
J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers
Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition
Endocr. Rev., April 1, 2006; 27(2): 101 - 140.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
S. R. Ojeda, A. Lomniczi, C. Mastronardi, S. Heger, C. Roth, A.-S. Parent, V. Matagne, and A. E. Mungenast
Minireview: The Neuroendocrine Regulation of Puberty: Is the Time Ripe for a Systems Biology Approach?
Endocrinology, March 1, 2006; 147(3): 1166 - 1174.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
H. M. Dungan, D. K Clifton, and R. A. Steiner
Minireview: Kisspeptin Neurons as Central Processors in the Regulation of Gonadotropin-Releasing Hormone Secretion
Endocrinology, March 1, 2006; 147(3): 1154 - 1158.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
S. Pompolo, A. Pereira, K. M. Estrada, and I. J. Clarke
Colocalization of Kisspeptin and Gonadotropin-Releasing Hormone in the Ovine Brain
Endocrinology, February 1, 2006; 147(2): 804 - 810.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
T. M. Plant, S. Ramaswamy, and M. J. DiPietro
Repetitive Activation of Hypothalamic G Protein-Coupled Receptor 54 with Intravenous Pulses of Kisspeptin in the Juvenile Monkey (Macaca mulatta) Elicits a Sustained Train of Gonadotropin-Releasing Hormone Discharges
Endocrinology, February 1, 2006; 147(2): 1007 - 1013.
[Abstract] [Full Text] [PDF]


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J. Neurosci.Home page
S.-K. Han, M. L. Gottsch, K. J. Lee, S. M. Popa, J. T. Smith, S. K. Jakawich, D. K. Clifton, R. A. Steiner, and A. E. Herbison
Activation of Gonadotropin-Releasing Hormone Neurons by Kisspeptin as a Neuroendocrine Switch for the Onset of Puberty
J. Neurosci., December 7, 2005; 25(49): 11349 - 11356.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
S. B. Seminara
We All Remember Our First Kiss: Kisspeptin and the Male Gonadal Axis
J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6738 - 6740.
[Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
W. S. Dhillo, O. B. Chaudhri, M. Patterson, E. L. Thompson, K. G. Murphy, M. K. Badman, B. M. McGowan, V. Amber, S. Patel, M. A. Ghatei, et al.
Kisspeptin-54 Stimulates the Hypothalamic-Pituitary Gonadal Axis in Human Males
J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6609 - 6615.
[Abstract] [Full Text] [PDF]


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J. Neurophysiol.Home page
A. C. Arai, Y.-F. Xia, E. Suzuki, M. Kessler, O. Civelli, and H.-P. Nothacker
Cancer Metastasis-Suppressing Peptide Metastin Upregulates Excitatory Synaptic Transmission in Hippocampal Dentate Granule Cells
J Neurophysiol, November 1, 2005; 94(5): 3648 - 3652.
[Abstract] [Full Text] [PDF]


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Physiol. Rev.Home page
N. Wettschureck and S. Offermanns
Mammalian G Proteins and Their Cell Type Specific Functions
Physiol Rev, October 1, 2005; 85(4): 1159 - 1204.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
M. Kinoshita, H. Tsukamura, S. Adachi, H. Matsui, Y. Uenoyama, K. Iwata, S. Yamada, K. Inoue, T. Ohtaki, H. Matsumoto, et al.
Involvement of Central Metastin in the Regulation of Preovulatory Luteinizing Hormone Surge and Estrous Cyclicity in Female Rats
Endocrinology, October 1, 2005; 146(10): 4431 - 4436.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
M. Tena-Sempere
Hypothalamic KiSS-1: The Missing Link in Gonadotropin Feedback Control?
Endocrinology, September 1, 2005; 146(9): 3683 - 3685.
[Full Text] [PDF]


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EndocrinologyHome page
J. T. Smith, M. J. Cunningham, E. F. Rissman, D. K Clifton, and R. A. Steiner
Regulation of Kiss1 Gene Expression in the Brain of the Female Mouse
Endocrinology, September 1, 2005; 146(9): 3686 - 3692.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
J. M. Castellano, V. M. Navarro, R. Fernandez-Fernandez, R. Nogueiras, S. Tovar, J. Roa, M. J. Vazquez, E. Vigo, F. F. Casanueva, E. Aguilar, et al.
Changes in Hypothalamic KiSS-1 System and Restoration of Pubertal Activation of the Reproductive Axis by Kisspeptin in Undernutrition
Endocrinology, September 1, 2005; 146(9): 3917 - 3925.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
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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EndocrinologyHome page
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.
[Full Text] [PDF]


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EndocrinologyHome page
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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Mol. Cell. Biol.Home page
N. Wettschureck, A. Moers, B. Wallenwein, A. F. Parlow, C. Maser-Gluth, and S. Offermanns
Loss of Gq/11 Family G Proteins in the Nervous System Causes Pituitary Somatotroph Hypoplasia and Dwarfism in Mice
Mol. Cell. Biol., March 1, 2005; 25(5): 1942 - 1948.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
R. K. Semple, J. C. Achermann, J. Ellery, I. S. Farooqi, F. E. Karet, R. G. Stanhope, S. O'Rahilly, and S. A. Aparicio
Two Novel Missense Mutations in G Protein-Coupled Receptor 54 in a Patient with Hypogonadotropic Hypogonadism
J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1849 - 1855.
[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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Proc. Natl. Acad. Sci. USAHome page
S. Messager, E. E. Chatzidaki, D. Ma, A. G. Hendrick, D. Zahn, J. Dixon, R. R. Thresher, I. Malinge, D. Lomet, M. B. L. Carlton, et al.
Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54
PNAS, February 1, 2005; 102(5): 1761 - 1766.
[Abstract] [Full Text] [PDF]


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EndocrinologyHome page
V. M. Navarro, J. M. Castellano, R. Fernandez-Fernandez, S. Tovar, J. Roa, A. Mayen, R. Nogueiras, M. J. Vazquez, M. L. Barreiro, P. Magni, et al.
Characterization of the Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide, the Natural Ligand of GPR54
Endocrinology, January 1, 2005; 146(1): 156 - 163.
[Abstract] [Full Text] [PDF]


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J. Physiol.Home page
V. M Navarro, R Fernandez-Fernandez, J. M Castellano, J Roa, A Mayen, M. L Barreiro, F Gaytan, E Aguilar, L Pinilla, C Dieguez, et al.
Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54
J. Physiol., December 1, 2004; 561(2): 379 - 386.
[Abstract] [Full Text] [PDF]




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