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Endocrinology Vol. 145, No. 9 4073-4077
Copyright © 2004 by The Endocrine Society

BRIEF COMMUNICATION

A Role for Kisspeptins in the Regulation of Gonadotropin Secretion in the Mouse

M. L. Gottsch, M. J. Cunningham, J. T. Smith, S. M. Popa, B. V. Acohido, W. F. Crowley, S. Seminara, D. K. Clifton and R. A. Steiner

Departments of Physiology & Biophysics (M.L.G., M.J.C., J.T.S., S.M.P., R.A.S.), Obstetrics & Gynecology (B.V.A., D.K.C., R.A.S.), and Biology (R.A.S.), University of Washington, Seattle, Washington 98195-7290; and the Massachusetts General Hospital (W.F.C., S.S.), Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Robert A. Steiner, Department of Physiology & Biophysics Health Sciences Building, G-424 School of Medicine University of Washington, Box 357290, 1959 Northeast Pacific Street, Seattle, Washington 98195-7290. E-mail: steiner{at}u.washington.edu.

Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54. Mutations or targeted disruptions in the GPR54 gene cause hypogonadotropic hypogonadism in humans and mice, suggesting that kisspeptin signaling may be important for the regulation of gonadotropin secretion. To examine the effects of kisspeptin-54 (metastin) and kisspeptin-10 (the biologically active C-terminal decapeptide) on gonadotropin secretion in the mouse, we administered the kisspeptins directly into the lateral cerebral ventricle of the brain and demonstrated that both peptides stimulate LH secretion. Further characterization of kisspeptin-54 demonstrated that it stimulated both LH and FSH secretion, at doses as low as 1 fmol; moreover, this effect was shown to be blocked by pretreatment with acyline, a potent GnRH antagonist. To learn more about the functional anatomy of kisspeptins, we mapped the distribution of KiSS-1 mRNA in the hypothalamus. We observed that KiSS-1 mRNA is expressed in areas of the hypothalamus implicated in the neuroendocrine regulation of gonadotropin secretion, including the anteroventral periventricular nucleus, the periventricular nucleus, and the arcuate nucleus. We conclude that kisspeptin-GPR54 signaling may be part of the hypothalamic circuitry that governs the hypothalamic secretion of GnRH.




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