Some articles are marked with asterisk as they represent recommended references relevant for the field and/or provide a comprehensive review of key features of Kiss1R that could not be further expanded in this article.
Parent, A.S., Franssen, D., Fudvoye, J., et al. Current changes in pubertal timing: revised vision in relation with environmental factors including endocrine disruptors. Endocr Dev 29 (2016), 174–184.
Day, F.R., Elks, C.E., Murray, A., et al. Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK Biobank study. Sci Rep, 5, 2015, 11208.
Lakshman, R., Forouhi, N.G., Sharp, S.J., et al. Early age at menarche associated with cardiovascular disease and mortality. J Clin Endocrinol Metab 94 (2009), 4953–4960.
Mascarenhas, M.N., Flaxman, S.R., Boerma, T., et al. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med, 9, 2012 e1001356.
Pinilla, L., Aguilar, E., Dieguez, C., et al. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev 92 (2012), 1235–1316.
Tena-Sempere, M., Huhtaniemi, I., Gonadotropins and gonadotropin receptors. Fauser, B.C.J.M., (eds.) Reproductive medicine –molecular, cellular and genetic fundamentals, 2003, Parthenon Publishing, New York, 225–244.
Herbison, A.E., Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat Rev Endocrinol 12 (2016), 452–466.
Vassilatis, D.K., Hohmann, J.G., Zeng, H., et al. The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci USA 100 (2003), 4903–4908.
Fang, Y., Kenakin, T., Liu, C., Editorial: orphan GPCRs as emerging drug targets. Front Pharmacol, 6, 2015, 295.
Lee, D.K., Nguyen, T., O'Neill, G.P., et al. Discovery of a receptor related to the galanin receptors. FEBS Lett 446 (1999), 103–107.
Ohtaki, T., Shintani, Y., Honda, S., et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 411 (2001), 613–617.
Muir, A.I., Chamberlain, L., Elshourbagy, N.A., et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem 276 (2001), 28969–28975.
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 276 (2001), 34631–34636.
de Roux, N., Genin, E., Carel, J.C., et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 100 (2003), 10972–10976.
Seminara, S.B., Messager, S., Chatzidaki, E.E., et al. The GPR54 gene as a regulator of puberty. N Engl J Med 349 (2003), 1614–1627.
Colledge, W.H., Transgenic mouse models to study Gpr54/kisspeptin physiology. Peptides 30 (2009), 34–41.
Garcia-Galiano, D., van Ingen Schenau, D., Leon, S., et al. Kisspeptin signaling is indispensable for neurokinin B, but not glutamate, stimulation of gonadotropin secretion in mice. Endocrinology 153 (2012), 316–328.
Mayer, C., Boehm, U., Female reproductive maturation in the absence of kisspeptin/GPR54 signaling. Nat Neurosci 14 (2011), 704–710.
Popa, S.M., Moriyama, R.M., Caligioni, C.S., et al. Redundancy in Kiss1 expression safeguards reproduction in the mouse. Endocrinology 154 (2013), 2784–2794.
Topaloglu, A.K., Tello, J.A., Kotan, L.D., et al. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 366 (2012), 629–635.
Pasquier, J., Lafont, A.G., Tostivint, H., et al. Comparative evolutionary histories of kisspeptins and kisspeptin receptors in vertebrates reveal both parallel and divergent features. Front Endocrinol (Lausanne), 3, 2012, 173.
Pasquier, J., Kamech, N., Lafont, A.G., et al. Molecular evolution of GPCRs: kisspeptin/kisspeptin receptors. J Mol Endocrinol 52 (2014), T101–T117.
Ringel, M.D., Hardy, E., Bernet, V.J., et al. Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells. J Clin Endocrinol Metab, 87, 2002, 2399.
Castano, J.P., Martinez-Fuentes, A.J., Gutierrez-Pascual, E., et al. Intracellular signaling pathways activated by kisspeptins through GPR54: do multiple signals underlie function diversity?. Peptides 30 (2009), 10–15.
Castellano, J.M., Navarro, V.M., Fernandez-Fernandez, R., et al. Ontogeny and mechanisms of action for the stimulatory effect of kisspeptin on gonadotropin-releasing hormone system of the rat. Mol Cell Endocrinol 257–258 (2006), 75–83.
Liu, X., Lee, K., Herbison, A.E., Kisspeptin excites gonadotropin-releasing hormone neurons through a phospholipase C/calcium-dependent pathway regulating multiple ion channels. Endocrinology 149 (2008), 4605–4614.
Wacker, J.L., Feller, D.B., Tang, X.B., et al. Disease-causing mutation in GPR54 reveals the importance of the second intracellular loop for class A G-protein-coupled receptor function. J Biol Chem 283 (2008), 31068–31078.
Wettschureck, N., Offermanns, S., Mammalian G proteins and their cell type specific functions. Physiol Rev 85 (2005), 1159–1204.
Babwah, A.V., Navarro, V.M., Ahow, M., et al. GnRH neuron-specific ablation of Galphaq/11 results in only partial inactivation of the neuroendocrine-reproductive axis in both male and female mice: in vivo evidence for kiss1r-coupled galphaq/11-independent GnRH secretion. J Neurosci 35 (2015), 12903–12916.
Ahow, M., Min, L., Pampillo, M., et al. KISS1R signals independently of Galphaq/11 and triggers LH secretion via the beta-arrestin pathway in the male mouse. Endocrinology 155 (2014), 4433–4446.
Navenot, J.M., Wang, Z., Chopin, M., et al. Kisspeptin-10-induced signaling of GPR54 negatively regulates chemotactic responses mediated by CXCR4: a potential mechanism for the metastasis suppressor activity of kisspeptins. Cancer Res 65 (2005), 10450–10456.
Millar, R.P., Babwah, A.V., KISS1R: hallmarks of an effective regulator of the neuroendocrine axis. Neuroendocrinology 101 (2015), 193–210.
Irwig, M.S., Fraley, G.S., Smith, J.T., et al. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 80 (2004), 264–272.
Higo, S., Honda, S., Iijima, N., et al. Mapping of kisspeptin receptor mRNA in the whole rat brain and its co-localisation with oxytocin in the paraventricular nucleus. J Neuroendocrinol, 2016, 28.
Pampillo, M., Camuso, N., Taylor, J.E., et al. Regulation of GPR54 signaling by GRK2 and {beta}-arrestin. Mol Endocrinol 23 (2009), 2060–2074.
Bianco, S.D., Vandepas, L., Correa-Medina, M., et al. KISS1R intracellular trafficking and degradation: effect of the Arg386Pro disease-associated mutation. Endocrinology 152 (2011), 1616–1626.
Garcia-Galiano, D., Pinilla, L., Tena-Sempere, M., Sex steroids and the control of the Kiss1 system: developmental roles and major regulatory actions. J Neuroendocrinol 24 (2012), 22–33.
Roa, J., Tena-Sempere, M., Connecting metabolism and reproduction: roles of central energy sensors and key molecular mediators. Mol Cell Endocrinol 397 (2014), 4–14.
Jacobi, J.S., Martin, C., Nava, G., et al. 17-Beta-estradiol directly regulates the expression of adrenergic receptors and kisspeptin/GPR54 system in GT1-7 GnRH neurons. Neuroendocrinology 86 (2007), 260–269.
Yang, J.A., Yasrebi, A., Snyder, M., et al. The interaction of fasting, caloric restriction, and diet-induced obesity with 17beta-estradiol on the expression of KNDy neuropeptides and their receptors in the female mouse. Mol Cell Endocrinol 437 (2016), 35–50.
Dudek, M., Kolodziejski, P.A., Pruszynska-Oszmalek, E., et al. Effects of high-fat diet-induced obesity and diabetes on Kiss1 and GPR54 expression in the hypothalamic-pituitary-gonadal (HPG) axis and peripheral organs (fat, pancreas and liver) in male rats. Neuropeptides 56 (2016), 41–49.
Ojeda, S.R., Skinner, M.K., Puberty in the rat. Knobil, E., Neill, J.D., (eds.) The physiology of reproduction, 2006, Raven Press, 2061–2126.
Kirilov, M., Clarkson, J., Liu, X., et al. Dependence of fertility on kisspeptin-Gpr54 signaling at the GnRH neuron. Nat Commun, 4, 2013, 2492.
Leon, S., Barroso, A., Vazquez, M.J., et al. Direct actions of kisspeptins on GnRH neurons permit attainment of fertility but are insufficient to fully preserve gonadotropic Axis activity. Sci Rep, 6, 2016, 19206.
Han, S.Y., McLennan, T., Czieselsky, K., et al. Selective optogenetic activation of arcuate kisspeptin neurons generates pulsatile luteinizing hormone secretion. Proc Natl Acad Sci USA 112 (2015), 13109–13114.
Clarkson, J., Han, S.Y., Piet, R., et al. Definition of the hypothalamic GnRH pulse generator in mice. Proc Natl Acad Sci USA 114 (2017), E10216–E10223.
Navarro, V.M., Castellano, J.M., 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 luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 145 (2004), 4565–4574.
Shahab, M., Mastronardi, C., Seminara, S.B., et al. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA 102 (2005), 2129–2134.
Navarro, V.M., Fernandez-Fernandez, R., Castellano, J.M., et al. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J Physiol 561 (2004), 379–386.
Clarkson, J., Han, S.K., Liu, X., et al. Neurobiological mechanisms underlying kisspeptin activation of gonadotropin-releasing hormone (GnRH) neurons at puberty. Mol Cell Endocrinol 324 (2010), 45–50.
Avendano, M.S., Vazquez, M.J., Tena-Sempere, M., Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty. Hum Reprod Update 23 (2017), 737–763.
Han, S.K., Gottsch, M.L., Lee, K.J., et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 25 (2005), 11349–11356.
Pineda, R., Garcia-Galiano, D., Roseweir, A., et al. Critical roles of kisspeptins in female puberty and preovulatory gonadotropin surges as revealed by a novel antagonist. Endocrinology 151 (2010), 722–730.
Guerriero, K.A., Keen, K.L., Millar, R.P., et al. Developmental changes in GnRH release in response to kisspeptin agonist and antagonist in female rhesus monkeys (Macaca mulatta): implication for the mechanism of puberty. Endocrinology 153 (2012), 825–836.
Okamura, H., Tsukamura, H., Ohkura, S., et al. Kisspeptin and GnRH pulse generation. Adv Exp Med Biol 784 (2013), 297–323.
Lehman, M.N., Coolen, L.M., Goodman, R.L., Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 151 (2010), 3479–3489.
Roa, J., Vigo, E., Castellano, J.M., et al. Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female rat. Endocrinology 147 (2006), 2864–2878.
Dhillo, W.S., Chaudhri, O.B., Thompson, E.L., et al. Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women. J Clin Endocrinol Metab 92 (2007), 3958–3966.
Castellano, J.M., Navarro, V.M., 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 146 (2005), 3917–3925.
Castellano, J.M., Bentsen, A.H., Mikkelsen, J.D., et al. Kisspeptins: bridging energy homeostasis and reproduction. Brain Res 1364 (2010), 129–138.
Sanchez-Garrido, M.A., Ruiz-Pino, F., Manfredi-Lozano, M., et al. Obesity-induced hypogonadism in the male: premature reproductive neuroendocrine senescence and contribution of Kiss1-mediated mechanisms. Endocrinology 155 (2014), 1067–1079.
Sanchez-Garrido, M.A., Ruiz-Pino, F., Manfredi-Lozano, M., et al. Metabolic and gonadotropic impact of sequential obesogenic insults in the female: influence of the loss of ovarian secretion. Endocrinology 156 (2015), 2984–2998.
Lopez, M., Tena-Sempere, M., Estrogens and the control of energy homeostasis: a brain perspective. Trends Endocrinol Metab 26 (2015), 411–421.
Manfredi-Lozano, M., Roa, J., Tena-Sempere, M., Connecting metabolism and gonadal function: novel central neuropeptide pathways involved in the metabolic control of puberty and fertility. Front Neuroendocrinol 48 (2018), 37–49.
Navarro, V.M., Tena-Sempere, M., Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nat Rev Endocrinol 8 (2012), 40–53.
Donato, J. Jr., Cravo, R.M., Frazao, R., et al. Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest 121 (2011), 355–368.
Teles, M.G., Bianco, S.D., Brito, V.N., et al. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 358 (2008), 709–715.
Brioude, F., Bouligand, J., Francou, B., et al. Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. PLoS One, 8, 2013, e53896.
Shimizu, K., Yonekawa, T., Yoshida, M., et al. Conformational change in the ligand-binding pocket via a KISS1R mutation (P147L) leads to isolated gonadotropin-releasing hormone deficiency. J Endocr Soc 1 (2017), 1259–1271.
Demirbilek, H., Ozbek, M.N., Demir, K., et al. Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families. Clin Endocrinol (Oxf) 82 (2015), 429–438.
Francou, B., Paul, C., Amazit, L., et al. Prevalence of KISS1 Receptor mutations in a series of 603 patients with normosmic congenital hypogonadotrophic hypogonadism and characterization of novel mutations: a single-centre study. Hum Reprod 31 (2016), 1363–1374.
Dhillo, W.S., Chaudhri, O.B., Patterson, M., et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 90 (2005), 6609–6615.
Chan, Y.M., Butler, J.P., Pinnell, N.E., et al. Kisspeptin resets the hypothalamic GnRH clock in men. J Clin Endocrinol Metab 96 (2011), E908–E915.
George, J.T., Veldhuis, J.D., Roseweir, A.K., et al. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab 96 (2011), E1228–E1236.
Jayasena, C.N., Nijher, G.M., Abbara, A., et al. Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clin Pharmacol Ther 88 (2010), 840–847.
Jayasena, C.N., Abbara, A., Comninos, A.N., et al. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. J Clin Invest 124 (2014), 3667–3677.
Abbara, A., Jayasena, C.N., Christopoulos, G., et al. Efficacy of Kisspeptin-54 to trigger oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization (IVF) therapy. J Clin Endocrinol Metab 100 (2015), 3322–3331.
Dandona, P., Dhindsa, S., Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab 96 (2011), 2643–2651.
George, J.T., Veldhuis, J.D., Tena-Sempere, M., et al. Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism. Clin Endocrinol (Oxf) 79 (2013), 100–104.
Roseweir, A.K., Kauffman, A.S., Smith, J.T., et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci 29 (2009), 3920–3929.
Witchel, S.F., Tena-Sempere, M., The Kiss1 system and polycystic ovary syndrome: lessons from physiology and putative pathophysiologic implications. Fertil Steril 100 (2013), 12–22.
Albers-Wolthers, C.H.J., de Gier, J., Walen, M., et al. In vitro and in vivo effects of kisspeptin antagonists p234, p271, p354, and p356 on GPR54 activation. PLoS One, 12, 2017 e0179156.
Liu, X., Herbison, A., Kisspeptin regulation of arcuate neuron excitability in kisspeptin receptor knockout mice. Endocrinology 156 (2015), 1815–1827.
Min, L., Leon, S., Li, H., et al. RF9 acts as a KISS1R agonist in vivo and in vitro. Endocrinology 156 (2015), 4639–4648.
Decourt, C., Robert, V., Anger, K., et al. A synthetic kisspeptin analog that triggers ovulation and advances puberty. Sci Rep, 6, 2016, 26908.
MacLean, D.B., Matsui, H., Suri, A., et al. Sustained exposure to the investigational Kisspeptin analog, TAK-448, down-regulates testosterone into the castration range in healthy males and in patients with prostate cancer: results from two phase 1 studies. J Clin Endocrinol Metab 99 (2014), E1445–E1453.
Gaytan, F., Gaytan, M., Castellano, J.M., et al. KiSS-1 in the mammalian ovary: distribution of kisspeptin in human and marmoset and alterations in KiSS-1 mRNA levels in a rat model of ovulatory dysfunction. Am J Physiol Endocrinol Metab 296 (2009), E520–E531.
Irfan, S., Ehmcke, J., Shahab, M., et al. Immunocytochemical localization of kisspeptin and kisspeptin receptor in the primate testis. J Med Primatol 45 (2016), 105–111.
Luque, R.M., Cordoba-Chacon, J., Gahete, M.D., et al. Kisspeptin regulates gonadotroph and somatotroph function in nonhuman primate pituitary via common and distinct signaling mechanisms. Endocrinology 152 (2011), 957–966.
Song, W.J., Mondal, P., Wolfe, A., et al. Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab 19 (2014), 667–681.
Tolson, K.P., Garcia, C., Yen, S., et al. Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. J Clin Invest 124 (2014), 3075–3079.
