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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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H. M. Dungan Lemko, D. K. Clifton, R. A. Steiner, and G. S. Fraley Altered response to metabolic challenges in mice with genetically targeted deletions of galanin-like peptide Am J Physiol Endocrinol Metab, September 1, 2008; 295(3): E605 - E612. [Abstract] [Full Text] [PDF] |
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L. M. Garcia-Segura, B. Lorenz, and L. L DonCarlos The role of glia in the hypothalamus: implications for gonadal steroid feedback and reproductive neuroendocrine output Reproduction, April 1, 2008; 135(4): 419 - 429. [Abstract] [Full Text] [PDF] |
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J. Pielecka-Fortuna, Z. Chu, and S. M. Moenter Kisspeptin Acts Directly and Indirectly to Increase Gonadotropin-Releasing Hormone Neuron Activity and Its Effects Are Modulated by Estradiol Endocrinology, April 1, 2008; 149(4): 1979 - 1986. [Abstract] [Full Text] [PDF] |
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J. Roa, E. Vigo, J. M. Castellano, F. Gaytan, V. M. Navarro, E. Aguilar, F. A. Dijcks, A. G. H. Ederveen, L. Pinilla, P. I. van Noort, et al. Opposite Roles of Estrogen Receptor (ER)-{alpha} and ER{beta} in the Modulation of Luteinizing Hormone Responses to Kisspeptin in the Female Rat: Implications for the Generation of the Preovulatory Surge Endocrinology, April 1, 2008; 149(4): 1627 - 1637. [Abstract] [Full Text] [PDF] |
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J. S. Kinsey-Jones, X. F. Li, S. M. Luckman, and K. T. O'Byrne Effects of Kisspeptin-10 on the Electrophysiological Manifestation of Gonadotropin-Releasing Hormone Pulse Generator Activity in the Female Rat Endocrinology, March 1, 2008; 149(3): 1004 - 1008. [Abstract] [Full Text] [PDF] |
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M. G. Teles, S. D.C. Bianco, V. N. Brito, E. B. Trarbach, W. Kuohung, S. Xu, S. B. Seminara, B. B. Mendonca, U. B. Kaiser, and A. C. Latronico A GPR54-Activating Mutation in a Patient with Central Precocious Puberty N. Engl. J. Med., February 14, 2008; 358(7): 709 - 715. [Abstract] [Full Text] [PDF] |
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A. L Filby, R. v. Aerle, J. Duitman, and C. R Tyler The Kisspeptin/Gonadotropin-Releasing Hormone Pathway and Molecular Signaling of Puberty in Fish Biol Reprod, February 1, 2008; 78(2): 278 - 289. [Abstract] [Full Text] [PDF] |
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R. L. Goodman, M. N. Lehman, J. T. Smith, L. M. Coolen, C. V. R. de Oliveira, M. R. Jafarzadehshirazi, A. Pereira, J. Iqbal, A. Caraty, P. Ciofi, et al. Kisspeptin Neurons in the Arcuate Nucleus of the Ewe Express Both Dynorphin A and Neurokinin B Endocrinology, December 1, 2007; 148(12): 5752 - 5760. [Abstract] [Full Text] [PDF] |
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S. B. Seminara Converging at Puberty's Hub Endocrinology, November 1, 2007; 148(11): 5145 - 5146. [Full Text] [PDF] |
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C. L. Roth, C. Mastronardi, A. Lomniczi, H. Wright, R. Cabrera, A. E. Mungenast, S. Heger, H. Jung, C. Dubay, and S. R. Ojeda Expression of a Tumor-Related Gene Network Increases in the Mammalian Hypothalamus at the Time of Female Puberty Endocrinology, November 1, 2007; 148(11): 5147 - 5161. [Abstract] [Full Text] [PDF] |
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W. S. Dhillo, O. B. Chaudhri, E. L. Thompson, K. G. Murphy, M. Patterson, R. Ramachandran, G. K. Nijher, V. Amber, A. Kokkinos, M. Donaldson, et al. Kisspeptin-54 Stimulates Gonadotropin Release Most Potently during the Preovulatory Phase of the Menstrual Cycle in Women J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3958 - 3966. [Abstract] [Full Text] [PDF] |
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R. M. Luque, R. D. Kineman, and M. Tena-Sempere Regulation of Hypothalamic Expression of KiSS-1 and GPR54 Genes by Metabolic Factors: Analyses Using Mouse Models and a Cell Line Endocrinology, October 1, 2007; 148(10): 4601 - 4611. [Abstract] [Full Text] [PDF] |
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D. Marot, I. Bieche, C. Aumas, S. Esselin, C. Bouquet, S. Vacher, G. Lazennec, M. Perricaudet, F. Kuttenn, R. Lidereau, et al. High tumoral levels of Kiss1 and G-protein-coupled receptor 54 expression are correlated with poor prognosis of estrogen receptor-positive breast tumors Endocr. Relat. Cancer, September 1, 2007; 14(3): 691 - 702. [Abstract] [Full Text] [PDF] |
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X. d'Anglemont de Tassigny, L. A. Fagg, J. P. C. Dixon, K. Day, H. G. Leitch, A. G. Hendrick, D. Zahn, I. Franceschini, A. Caraty, M. B. L. Carlton, et al. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene PNAS, June 19, 2007; 104(25): 10714 - 10719. [Abstract] [Full Text] [PDF] |
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S. Yamada, Y. Uenoyama, M. Kinoshita, K. Iwata, K. Takase, H. Matsui, S. Adachi, K. Inoue, K.-I. Maeda, and H. Tsukamura Inhibition of Metastin (Kisspeptin-54)-GPR54 Signaling in the Arcuate Nucleus-Median Eminence Region during Lactation in Rats Endocrinology, May 1, 2007; 148(5): 2226 - 2232. [Abstract] [Full Text] [PDF] |
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A. S. Kauffman, M. L. Gottsch, J. Roa, A. C. Byquist, A. Crown, D. K. Clifton, G. E. Hoffman, R. A. Steiner, and M. Tena-Sempere Sexual Differentiation of Kiss1 Gene Expression in the Brain of the Rat Endocrinology, April 1, 2007; 148(4): 1774 - 1783. [Abstract] [Full Text] [PDF] |
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T. J. Greives, A. O. Mason, M.-A. L. Scotti, J. Levine, E. D. Ketterson, L. J. Kriegsfeld, and G. E. Demas Environmental Control of Kisspeptin: Implications for Seasonal Reproduction Endocrinology, March 1, 2007; 148(3): 1158 - 1166. [Abstract] [Full Text] [PDF] |
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E. Vigo, J. Roa, M. Lopez, J. M. Castellano, R. Fernandez-Fernandez, V. M. Navarro, R. Pineda, E. Aguilar, C. Dieguez, L. Pinilla, et al. Neuromedin S as Novel Putative Regulator of Luteinizing Hormone Secretion Endocrinology, February 1, 2007; 148(2): 813 - 823. [Abstract] [Full Text] [PDF] |
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B. Lee, J. K. Hiney, M. D. Pine, V. K. Srivastava, and W. L. Dees Manganese stimulates luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site and mechanism of action J. Physiol., February 1, 2007; 578(3): 765 - 772. [Abstract] [Full Text] [PDF] |
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J. Clarkson and A. E. Herbison Postnatal Development of Kisspeptin Neurons in Mouse Hypothalamus; Sexual Dimorphism and Projections to Gonadotropin-Releasing Hormone Neurons Endocrinology, December 1, 2006; 147(12): 5817 - 5825. [Abstract] [Full Text] [PDF] |
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F. Cerrato, J. Shagoury, M. Kralickova, A. Dwyer, J. Falardeau, M. Ozata, G. Van Vliet, P. Bouloux, J. E Hall, F. J Hayes, et al. Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S3 - S10. [Abstract] [Full Text] [PDF] |
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W. S. Dhillo, P. Savage, K. G. Murphy, O. B. Chaudhri, M. Patterson, G. M. Nijher, V. M. Foggo, G. S. Dancey, H. Mitchell, M. J. Seckl, et al. Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E878 - E884. [Abstract] [Full Text] [PDF] |
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E. L. Thompson, K. G. Murphy, M. Patterson, G. A. Bewick, G. W. H. Stamp, A. E. Curtis, J. H. Cooke, P. H. Jethwa, J. F. Todd, M. A. Ghatei, et al. Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E1074 - E1082. [Abstract] [Full Text] [PDF] |
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J. M. Castellano, M. Gaytan, J. Roa, E. Vigo, V. M. Navarro, C. Bellido, C. Dieguez, E. Aguilar, J. E. Sanchez-Criado, A. Pellicer, et al. Expression of KiSS-1 in Rat Ovary: Putative Local Regulator of Ovulation? Endocrinology, October 1, 2006; 147(10): 4852 - 4862. [Abstract] [Full Text] [PDF] |
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J. M. Castellano, V. M. Navarro, R. Fernandez-Fernandez, J. Roa, E. Vigo, R. Pineda, C. Dieguez, E. Aguilar, L. Pinilla, and M. Tena-Sempere Expression of Hypothalamic KiSS-1 System and Rescue of Defective Gonadotropic Responses by Kisspeptin in Streptozotocin-Induced Diabetic Male Rats Diabetes, September 1, 2006; 55(9): 2602 - 2610. [Abstract] [Full Text] [PDF] |
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M. Tena-Sempere GPR54 and kisspeptin in reproduction Hum. Reprod. Update, September 1, 2006; 12(5): 631 - 639. [Abstract] [Full Text] [PDF] |
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J. T. Smith, S. M. Popa, D. K. Clifton, G. E. Hoffman, and R. A. Steiner Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J. Neurosci., June 21, 2006; 26(25): 6687 - 6694. [Abstract] [Full Text] [PDF] |
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S. Tovar, M. J. Vazquez, V. M. Navarro, R. Fernandez-Fernandez, J. M. Castellano, E. Vigo, J. Roa, F. F. Casanueva, E. Aguilar, L. Pinilla, et al. Effects of Single or Repeated Intravenous Administration of Kisspeptin upon Dynamic LH Secretion in Conscious Male Rats Endocrinology, June 1, 2006; 147(6): 2696 - 2704. [Abstract] [Full Text] [PDF] |
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J. Roa, E. Vigo, J. M. Castellano, V. M. Navarro, R. Fernandez-Fernandez, F. F. Casanueva, C. Dieguez, E. Aguilar, L. Pinilla, and M. Tena-Sempere Hypothalamic Expression of KiSS-1 System and Gonadotropin-Releasing Effects of Kisspeptin in Different Reproductive States of the Female Rat Endocrinology, June 1, 2006; 147(6): 2864 - 2878. [Abstract] [Full Text] [PDF] |
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V. M. Navarro, R. Fernandez-Fernandez, R. Nogueiras, E. Vigo, S. Tovar, N. Chartrel, O. Le Marec, J. Leprince, E. Aguilar, L. Pinilla, et al. Novel role of 26RFa, a hypothalamic RFamide orexigenic peptide, as putative regulator of the gonadotropic axis J. Physiol., May 15, 2006; 573(1): 237 - 249. [Abstract] [Full Text] [PDF] |
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S. B. Seminara, M. J. DiPietro, S. Ramaswamy, W. F. Crowley Jr., and T. M. Plant Continuous Human Metastin 45-54 Infusion Desensitizes G Protein-Coupled Receptor 54-Induced Gonadotropin-Releasing Hormone Release Monitored Indirectly in the Juvenile Male Rhesus Monkey (Macaca mulatta): A Finding with Therapeutic Implications Endocrinology, May 1, 2006; 147(5): 2122 - 2126. [Abstract] [Full Text] [PDF] |
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J. T Smith, D. K Clifton, and R. A Steiner Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling. Reproduction, April 1, 2006; 131(4): 623 - 630. [Abstract] [Full Text] [PDF] |
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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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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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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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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. [Abstract] [Full Text] [PDF] |
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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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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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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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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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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. [Full Text] [PDF] |
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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. [Abstract] [Full Text] [PDF] |
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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. [Abstract] [Full Text] [PDF] |
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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. [Full Text] [PDF] |
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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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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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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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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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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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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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