Kisspeptin Can Stimulate Gonadotropin-releasing Hormone (GnRH) Release by a Direct Action at GnRH Nerve Terminals

Overview

Journal Endocrinology

Publisher Oxford University Press

Specialty Endocrinology

Date 2008 May 3

PMID 18450966

Citations 94

Authors

Xavier dAnglemont de Tassigny

Lisa A Fagg

Mark B L Carlton

William H Colledge

Affiliations

Soon will be listed here.

Abstract

The G protein-coupled receptor GPR54, and its peptide ligand kisspeptin (Kp), are crucial for the induction and maintenance of mammalian reproductive function. GPR54 is expressed by GnRH neurons and is directly activated by Kp to stimulate GnRH release. We hypothesized that Kp may be able to act at the GnRH nerve terminals located in the mediobasal hypothalamus (MBH) region. To test this hypothesis, we used organotypic culture of MBH explants challenged with Kp, followed by RIA to detect GnRH released into the cultured medium. Kp stimulation for 1 h induced GnRH release from wild-type male MBH in a dose-dependent manner, whereas this did not occur in MBH explants isolated from Gpr54 null mice. Continuous Kp stimulation caused a sustained GnRH release for 4 h, followed by a decrease of GnRH release, suggesting a desensitization of GPR54 activity. Tetrodotoxin did not alter the Kp-induced GnRH release, indicating that Kp can act directly at the GnRH nerve terminals. To localize Gpr54 expression within the MBH, we used transgenic mice, in which Gpr54 expression is tagged with an IRES-LacZ reporter gene and can be visualized by beta-galactosidase staining. Gpr54 expression was detected outside of the median eminence, in the pars tuberalis. In conclusion, our results provide evidence for a potent stimulating effect of Kp at GnRH nerve terminals in the MBH of the mouse. This study suggests a new point at which Kp can act on GnRH neurons.

Citing Articles

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References

Seminara S, Messager S, Chatzidaki E, Thresher R, Acierno Jr J, Shagoury J . The GPR54 gene as a regulator of puberty. N Engl J Med. 2003; 349(17):1614-27. DOI: 10.1056/NEJMoa035322. View

Clarkson J, Herbison A . Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology. 2006; 147(12):5817-25. PMC: 6098691. DOI: 10.1210/en.2006-0787. View

Herbison A . Multimodal influence of estrogen upon gonadotropin-releasing hormone neurons. Endocr Rev. 1998; 19(3):302-30. DOI: 10.1210/edrv.19.3.0332. View

Shahab M, Mastronardi C, Seminara S, Crowley W, Ojeda S, Plant T . Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci U S A. 2005; 102(6):2129-34. PMC: 548549. DOI: 10.1073/pnas.0409822102. View

Han S, Gottsch M, Lee K, Popa S, Smith J, Jakawich S . Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci. 2005; 25(49):11349-56. PMC: 6725899. DOI: 10.1523/JNEUROSCI.3328-05.2005. View

Baker B, Yu Y . Immunocytochemical analysis of cells in the pars tuberalis of the rat hypophysis with antisera to hormones of the pars distalis. Cell Tissue Res. 1975; 156(4):443-9. DOI: 10.1007/BF00225104. View

Dhillo W, Chaudhri O, Patterson M, Thompson E, Murphy K, Badman M . Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005; 90(12):6609-15. DOI: 10.1210/jc.2005-1468. View

Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K . Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001; 411(6837):613-7. DOI: 10.1038/35079135. View

Seminara S, DiPietro M, Ramaswamy S, Crowley Jr W, Plant T . 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. 2006; 147(5):2122-6. DOI: 10.1210/en.2005-1550. View

10.

Navarro V, Castellano J, Fernandez-Fernandez R, Tovar S, Roa J, Mayen A . Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology. 2004; 146(1):156-63. DOI: 10.1210/en.2004-0836. View

11.

Beauvillain J, Tramu G . Immunocytochemical demonstration of LH-RH, somatostatin, and ACTH-like peptide in osmium-postfixed, resin-embedded median eminence. J Histochem Cytochem. 1980; 28(9):1014-7. DOI: 10.1177/28.9.6157712. View

12.

Colledge W . GPR54 and puberty. Trends Endocrinol Metab. 2004; 15(9):448-53. DOI: 10.1016/j.tem.2004.09.008. View

13.

Schulz M, Engelhardt B . The circumventricular organs participate in the immunopathogenesis of experimental autoimmune encephalomyelitis. Cerebrospinal Fluid Res. 2005; 2:8. PMC: 1262737. DOI: 10.1186/1743-8454-2-8. View

14.

Ramaswamy S, Seminara S, Pohl C, DiPietro M, Crowley Jr W, Plant T . Effect of continuous intravenous administration of human metastin 45-54 on the neuroendocrine activity of the hypothalamic-pituitary-testicular axis in the adult male rhesus monkey (Macaca mulatta). Endocrinology. 2007; 148(7):3364-70. DOI: 10.1210/en.2007-0207. View

15.

Thompson E, Patterson M, Murphy K, Smith K, Dhillo W, Todd J . Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol. 2004; 16(10):850-8. DOI: 10.1111/j.1365-2826.2004.01240.x. View

16.

Patterson M, Murphy K, Thompson E, Patel S, Ghatei M, Bloom S . Administration of kisspeptin-54 into discrete regions of the hypothalamus potently increases plasma luteinising hormone and testosterone in male adult rats. J Neuroendocrinol. 2006; 18(5):349-54. DOI: 10.1111/j.1365-2826.2006.01420.x. View

17.

Gottsch M, Clifton D, Steiner R . Kisspepeptin-GPR54 signaling in the neuroendocrine reproductive axis. Mol Cell Endocrinol. 2006; 254-255:91-6. DOI: 10.1016/j.mce.2006.04.030. View

18.

Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T . Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun. 2004; 320(2):383-8. DOI: 10.1016/j.bbrc.2004.05.185. View

19.

Messager S, Chatzidaki E, Ma D, Hendrick A, Zahn D, Dixon J . Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A. 2005; 102(5):1761-6. PMC: 545088. DOI: 10.1073/pnas.0409330102. View

20.

Plant T, Ramaswamy S, DiPietro M . 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. 2005; 147(2):1007-13. DOI: 10.1210/en.2005-1261. View