The roles of kisspeptins and G protein-coupled receptor-54 in pubertal development

Current Opinion in Pediatrics

Volumn 18, Issue 4, 2006, Pages 442-447

  Tena Sempere, Manuel ^a  

^a UNIVERSITY OF CÓRDOBA   (Spain)

Author keywords

G protein coupled receptor 54; Gonadotropin releasing hormone; Gonadotropins; Hypogonadism; KiSS 1; Kisspeptin; Puberty

Indexed keywords

G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR 54; GENE PRODUCT; GONADORELIN; GONADOTROPIN; KISSPEPTIN; PEPTIDE DERIVATIVE; STEROID; UNCLASSIFIED DRUG;

GENE; GENE EXPRESSION; GENE IDENTIFICATION; GENE MUTATION; GONADOTROPIN RELEASE; GPR54 GENE; HORMONAL REGULATION; HORMONE RELEASE; HUMAN; HYPOGONADOTROPIC HYPOGONADISM; HYPOTHALAMUS; KISS GENE; MONKEY; NONHUMAN; NUTRITION; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; PUBERTY; RECEPTOR UPREGULATION; REPRODUCTION; REVIEW; RODENT; SIGNAL TRANSDUCTION;

ANIMALS; BIOTRANSFORMATION; ENERGY METABOLISM; GONADOTROPINS; HUMANS; PUBERTY; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR PROTEINS;

EID: 33747500559     PISSN: 10408703     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.mop.0000236396.79580.cc     Document Type: Review

References (36)

1. Ojeda SR, Skinner MK. Puberty in the rat. In: Neill JD, editor. The physiology of reproduction, 3rd ed. San Diego, CA: Academic Press/Elsevier; 2005. pp. 2061-2126.
2. Tena-Sempere M, Huhtaniemi I. Gonadotropins and gonadotropin receptors. In: Fauser BCJM, editor. Reproductive medicine: molecular, cellular and genetic fundamentals. New York: Parthenon Publishing; 2003. pp. 225-244.
3. Ojeda SR, Lomniczi A, Mastronardi C, et al. The neuroendocrine regulation of puberty: is the time ripe for a systems biology approach? Endocrinology 2006; 147:1166-1174. Using a system biology approach, the authors provide a comprehensive and updated review on the mechanisms of puberty onset, with special emphasis on description of glial-to-neuron and neuron-to-neuron circuits responsible for excitatory and inhibitory control of GnRH pulse generator.
4. Casanueva FF, Dieguez C. Neuroendocrine regulation and actions of leptin. Front Neuroendocrinol 1999; 20:317-363.
5. Barreiro ML, Tena-Sempere M. Ghrelin and reproduction: a novel signal linking energy status and fertility? Mol Cell Endocrinol 2004; 226:1-9.
6. Seeley RJ, York DA. Fuel sensing and the central nervous system (CNS): implications for the regulation of energy balance and the treatment of obesity. Obes Rev 2005; 6:259-265.
7. Cunningham MJ, Clifton DK, Steiner RA. Leptin's actions on the reproductive axis: perspectives and mechanisms. Biol Reprod 1999; 60:616-622.
8. Lee JH, Miele ME, Hicks DJ, et al. KiSS-1, a novel malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 1996; 88:1731-1737.
9. Kotani M, Detheux M, Vandenbogaerde A, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001; 276:34631-34636.
10. Ohtaki T, Shintani Y, Honda S, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G protein-coupled receptor. Nature 2001; 411:613-617.
11. Muir AI, Chamberlain L, Elshourbagy NA, et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem 2001; 276:28969-28975.
12. de Roux N, Genin E, Carel JC, et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003; 100:10972-10976.
13. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. New Engl J Med 2003; 349:1614-1627.
14. Funes S, Hendrick JA, Vassileva G, et al. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biophys Res Commun 2003; 312:1357-1363.
15. Messager S. Kisspeptin and its receptor: new gatekeepers of puberty. J Neuroendocrinol 2005; 17:687-688. Short essay, appearing as a Neuroendocrinology Briefing, summarizing some of the most striking aspects of kisspeptin function as gatekeeper of puberty onset, written by one of the scientists who created the GPR54 null mouse.
16. Gottsch ML, Cunningham MJ, Smith JT, et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 2004; 145:4073-4077.
17. Matsui H, Takatsu Y, Kumano S, et al. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 2004; 320:383-388.
18. Navarro VM, Castellano JM, Fernandez-Fernandez R, et al. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor GPR54 in rat hypothalamus and potent LH releasing activity of KiSS-1 peptide. Endocrinology 2004; 145:4565-4574.
19. Thompson EL, Patterson M, Murphy KG, et al. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamo-pituitary-gonadal axis. J Neuroendocrinol 2004; 16:850-858.
20. Navarro VM, Castellano JM, Fernandez-Fernandez R, et al. Characterization of the potent LH releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology 2005; 146:156-163. This is a comprehensive study on the luteinizing hormone-releasing effects of kisspeptin-10, after central and peripheral administration, in male rats. Dose-response curves in vivo are provided, and the interplay of kisspeptin, GnRH and other neurotransmitters involved in luteinizing hormone secretion, such as glutamate and nitric oxide, is explored.
21. Navarro VM, Castellano JM, Fernandez-Fernandez R, et al. Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat. Endocrinology 2005; 146:1689-1697. This is the first detailed analysis of the FSH-releasing effects of kisspeptin-10 in male rats. Comparative dose-response curves for luteinizing hormone and FSH effects of kisspeptin are shown. In addition, the interplay of kisspeptin, GnRH and other neurotransmitters (glutamate, nitric oxide) in the context of FSH secretion is explored.
22. Messager S, Chatzidaki EE, Ma D, Hendrick AG, et al. Kisspeptin directly stimulates gonadotropin-releasing hormone secretion via G protein-coupled receptor 54. Proc Natl Acad Sci U S A 2005; 102:1761-1766. This study is the first demonstration of the ability of kisspeptin to elicit GnRH release in vivo and to evoke luteinizing hormone secretion in the sheep. In addition, using GPR54 null mice, it provides conclusive evidence that the luteinizing hormone-releasing effects of kisspeptin are conducted via GPR54.
23. Shahab M, Mastronardi C, Seminara SB, et al. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci U S A 2005; 102:2129-2134. This is the first report of the capacity of kisspeptin to evoke luteinizing hormone secretion (after central and intravenous injection) in primates. This study also contains expression analyses showing that hypothalamic expression of GPR54 and KiSS-1 genes is increased in male and female monkeys along pubertal maturation.
24. Tovar S, Vazquez MJ, Navarro VM, et al. Effects of single or repeated intravenous administration of kisspeptin upon dynamic LH secretion in conscious male rat. Endocrinology 2006; 147:2696-2704. This is a detailed analysis of the effects of intravenous administration of kisspeptin-10, either after single or repeated injections, upon luteinizing hormone secretion in freely moving rats. This study reports the ability of very low (0.1 μg) doses of kisspeptin (intravenous) to stimulate luteinizing hormone secretion in the rat.
25. Plant TM, Ramaswamy S, DiPietro MJ. Repetitive administration 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 2006; 147:1007-1013. This paper describes the ability of repeated boluses (low doses) of kisspeptin to elicit a train of GnRH pulses in immature (juvenile) monkeys, reminiscent of what is observed at normal puberty. This suggests that activation of GPR54 is able to recapitulate the neuroendocrine events responsible for puberty onset in primates.
26. Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005; 90:6609-6615. This is the first demonstration of the capacity of metastin (kisspeptin-54) to elicit luteinizing hormone secretion in humans (healthy male volunteers).
27. Irwig MS, Fraley GS, Smith JT, et al. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1mRNA in the male rat. Neuroendocrinology 2004; 80:264-272.
28. Han SK, Gottsch ML, Lee KJ, et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 2005; 25:11349-11356. This elegant study, combining electrophysiological recordings, in-situ hybridization and hormonal tests, demonstrates that kisspeptin can induce the sustained activation of GnRH neurons, whose responsiveness to kisspeptin increases along postnatal development. Thus, puberty onset would derive from a combination of enhanced KiSS-1 input and increased kisspeptin responsiveness at GnRH neurons.
29. Castellano JM, Navarro VM, Fernandez-Fernandez R, et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology 2005; 146:3917-3925. This study is the first to provide evidence for decreased hypothalamic expression of KiSS-1 in conditions of negative energy balance. In addition, this paper demonstrates that kisspeptin administration is able to elicit potent GnRH and luteinizing hormone responses in fasted animals, and to rescue defective puberty onset in female rats at undernutrition.
30. Navarro VM, Fernandez-Fernandez R, Castellano JM, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J Physiol 2004; 561:379-386.
31. Pompolo S, Pereira A, Estrada KM, Clarke IJ. Colocalization of kisspeptin and gonadotropin-releasing hormone in the ovine brain. Endocrinology 2006; 147:804-810. This recent study provides a detailed immunohistochemical analysis of kisspeptin distribution in the sheep brain, and is the first to demonstrate an increase in kisspeptin immunoreactivity following gonadectomy. There are slight discrepancies with data previously reported in rodents, as they show that GnRH neurons in sheep colocalize kisspeptin, which might operate as hypophysiotropic factor via portal transport.
32. Kennedy GC, Mitra J. Body weight and food intake as initiating factors for puberty in the rat. J Physiol 1963; 166:408-418.
33. ••]. This article also describes that leptin-deficient ob/ob mice have lower hypothalamic KiSS-1 mRNA levels, which can be partially restored by leptin administration.
34. Smith JT, Dungan HM, Stoll EA, et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 2005; 146:2976-2984. Provides conclusive evidence for the involvement of hypothalamic KiSS-1 in the feedback control of gonadotropin secretion by gonadal steroids. Moreover, it demonstrates a predominant role of estrogen in the control of KiSS-1 gene expression at the hypothalamus, which is carried out in a nucleus-specific manner: inhibition at the arcuate nucleus; stimulation at the AVPV.
35. Smith JT, Cunningham MJ, Rissman EF, et al. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 2005; 146:3686-3692. Provides conclusive evidence for the involvement of hypothalamic KiSS-1 in the feedback control of gonadotropin secretion by gonadal steroids. Moreover, it demonstrates a predominant role of estrogen in the control of KiSS-1 gene expression at the hypothalamus, which is carried out in a nucleus-specific manner: inhibition at the arcuate nucleus; stimulation at the AVPV.
36. Dungan HM, Clifton DK, Steiner RA. Kisspeptin neurons as central processors in the regulation of GnRH secretion. Endocrinology 2006; 147:1166-1174. Excellent review summarizing the most recent developments in the field of kisspeptin physiology, with special attention to its role in feedback control of gonadotropins. It provides a comprehensive model for the integration of KiSS-1 neurons in the neuroendocrine network controlling reproduction, as essential processors in the regulation of GnRH secretion.