Kisspeptin, its Localization and Physiological Functions in Primates: A Review

Transcription

1 World Journal of Zoology 10 (2): , 2015 ISSN IDOSI Publications, 2015 DOI: /idosi.wjz Kisspeptin, its Localization and Physiological Functions in Primates: A Review Ghulam Nabi, Hazir Muhammad, Sardar Ali and Sami Ullah 1 Department of Animal Sciences, Laboratory Reproductive Neuro-Endocrinolgy, Quaid-i-Azam University, Islamabad, Pakistan 2 Department of Biotechnology, University of Malakand, Pakistan 3 Department of Microbiology, KUST, Pakistan 4 Department of Zoology, Islamia College University of Peshawar, Pakistan Abstract: Neuropeptide kisspeptin is considered a key regulator of reproductive system and a gate keeper of puberty. It expresses in a wide range of animal species both in the brain and other parts of the body. It is encoded by KISS1 gene and acts through GPR54 receptor. Kisspeptin has a wide range of physiological functions in the body. Inactivating or precocious activating mutations of either KISS1 or KISS1R gene can leads to serious health consequences. This review focuses on the brief introduction, localization and various physiological functions of kisspeptin in mammals. Key words: Kisspeptin Kiss1 Neuropeptide Puberty INTRODUCTION [13], neuromodulation [14-15], muscular contraction [16] and cardio-excitatory function [17-19]. Neuropeptide kisspeptin is a key regulator of Immunocytochemistry has shown the expression of reproductive system. Kisspeptin is encoded by a these peptides in vertebrates like amphibians, fishes metastasis suppressor gene called KISS1 [1]. Kisspeptin and birds [20]. In mammals RF-amide has a pivotal role in is found in human plasma andits concentration increases neuroendocrine functions [20-22]. during gestation [2]. Kisspeptin acts as a tumor Kisspeptin-54, -14, -13 and -10 (indicating the number metastasis suppressor [3].It contains 145-amino acids and of amino acids) are the members of kisspeptin family. belongs to RF-amide family of neuropeptides [1, 3-5]. All these are encoded by KISS1 gene. The precursor KISS1 is present on long arm of chromosome1 at the molecule called preprokisspeptin is enzymatically split position of 1q32. KISS1 gene manufactures a 145- amino into smaller naturally active C-terminal amide group in acids precursor molecule. A 54-amino acids kisspeptin post-translational changes resulting into kisspeptins. (kisspeptin-54), the product of proteolytic processof All the kisspeptin family members possess equal efficacy precursor molecule, is crucial for mammalian puberty and and affinity for kisspeptin receptor. This is because all the fertility. Lack of KISS1 or kisspeptin receptor (KISS1R) members possess a C terminal decapeptide which is genes causes hypogonadotropichypogonadism in essential for binding and provocation of kisspeptin humans and rodents [6]. Further cleavage of kisspeptin-54 receptor [3-5]. Kisspeptin carried out its function via a leads to the synthesis of kisspeptin-14, -13 and -10. They receptor called G- protein couple receptor (GPR54) or are differentiated by peptide length [7-10]. AXOR12 [3, 5]. In rat brain tissues an orphan G-protein The RF-amide neuropeptides terminate in -Arg-Phe- couple receptor (GPR54) was recognized for kisspeptin NH2motif [11]. RF-amides were first recognized in [23]. Latter researches identified kisspeptin receptors in Mollusca s. Latter on it was found also in other other species [24]. According to the rules of nomenclature vertebrates that peptides containing RF-amide motif at committee, International Union of Basic and Clinical their C-terminus were present [12]. RF-amide in Pharmacology (NC-IUPHAR) suggests the abbreviation, invertebrates has many functions such as locomotion KISS1R for kisspeptin receptor and KISS1 for the peptide. Corresponding Author: Ghulam Nabi, Department of Animal Sciences, Laboratory Reproductive Neuro-endocrinolgy, Quaid-i-Azam University, Islamabad, Pakistan. Mob:

2 Gene names should be italicized and consistent with the Human Genome Organization (HUGO), KISS1 to the peptide gene and KISSIR to the receptor gene, with lower case letter used for nonhuman species [24-25]. Kisspeptin Distribution: Using specific antibodies, cdna and RNA probes against kisspeptin, it was found that kisspeptin cells were present in the arcuate (ARC), preoptic area (POA) and median eminence (ME) of humans [26-27] and rhesus monkey, while bed nucleus of the striaterminalis (BNST) only in rhesus monkey [28-29]. In mouse these cells were located in the ARC, POA, rostral periventricular region of the third ventricle (RP3V), dorsal medial nucleus of hypothalamus (DMH), medial amygdala and BNST [30-31]. In rats, kisspeptin cells were localized to ARC, RP3V, ventro medial hypothalamus (VMH), medial amygdala and BNST [32-33]. In hamsters only in the ARC and RP3V [34], while in the guinea pig, kisspeptin cells were distributed in ARC, RP3V and DMH [35]. Similarly kisspeptin cells also expressed in the ARC, POA, DMH and VMH of sheep [36], goat (except DMH and VMH) [37] and horse (except VMH) [38]. In the mouse kisspeptin cells are also present in the neocortex, insular cortex, piriform cortex and lateral septum [30-31]. Similarly, in sheep kisspeptin cells are located in intermediate and caudal periventricular area [35]. On the other hand, kisspeptin fibers are also expressed in the ARC and POA of human [27], rhesus monkey [28], rat [32], mouse [31], hamster [39], guinea pig [35], sheep [40,41], goat [37] and horse [38]. In human beside ARC and POA, kisspeptin fibers are also expressed in RP3V, external and internal median eminence, PVN, VMH, DMH and lateral septum [27]. In rats kisspeptins existence has been observed in various parts of spinal cord and medulla oblongata suggesting, its role in controlling autonomic and sensory functions [42]. Kisspeptin expression is also present in human ganglionic cells and rat superior cervical ganglia [43]. Kisspeptin is also highly expressed in numerous peripheral regions including, placenta of rat and human [44], pituitary, small intestine, thymus, spleen, lung, stomach, kidney, liver, adrenal gland, vessels, adipose tissue [1, 4-5, 45-47] ovary [48], testis [3], pancreas [49], endothelial cells of the aorta, coronary artery and umbilical vein [50]. In mammals major population of kisspeptin cells have been observed in different areas of hypothalamus [51]. In rodents entire kisspeptin cells are present in rostral-caudal region of hypothalamus [52-53]. In sheep and monkeys, kisspeptin cells are frequently localized to caudal and middle region [40, 54]. Kisspeptin Receptor Distribution: Kisspeptin receptor is a G-protein coupled receptor. It belongs to the sub-family of Gq/11 proteins [4,5]. In human the KISSIR is confined to chromosomal site 19p13.3 [3]. Its mrna expressions are found in medial basal hypothalamus (MBH), POA, ARC, hypothalamus, medial amygdala, locus coeruleus, thalamus, substantial nigra, cingulate gyrus and anterior pituitary gland [4]. KISS1R is also expressed in testes especially in seminiferous tubules, round spermatocytes, Sertoli cells and spermatids but absent in Leydig cells, suggesting a role of kisspeptin in spermatogenesis via paracrine/autocrine action [55]. In human mature spermatozoa, kisspeptin and its receptors are located on equatorial section, neck region and slightly in mid- piece [56-58]. Kisspeptin Gene Regulation: Kisspeptin gene is mainly regulated by testosterone and estradiol feedback effects. Kisspeptin neurons in rodents are limited to anteroventral periventricular nucleus (AVPV) and ARC. Kiss1 gene expression in the ARC is suppressed by estradiol. In female and male mice kiss1mrna level is reduced by administering estradiol [59-60]. Similarly in female rats the level of Kiss1mRNA in ARC is negatively regulated by treating with progesterone and estradiol [53]. In the AVPV and ARC of female rat and mice, all kiss1 neurons express ERá [53, 61]. Ovarectomy in sheep stimulates the expression of kiss1 mrna and this effect is prevented by replacing estradiol [41, 62]. ERá and androgen receptor (AR) mediate negative feedback regulation of the kiss1gene in ARC of male mouse [60]. In male hypothalamus kiss1 mrna expression is regulated by testosterone. In castrated mice, testosterone treatment inhibits the rise of ARC kiss1 mrna. The expression of kiss1 mrna in AVPV is reduces by castration but is stimulated by testosterone [59]. In male AVPV and ARC most of the kisspeptin neurons co-express AR and ERá [59, 63]. In addition to gonadal steroids, some other hormones also influence kiss1 gene expression. Leptin stimulates the kisspeptin neurons of ARC nucleus. It has been reported that the expression of ARC kiss1 is low in male mice having no active leptin gene. On the other hand expression is restored partially by treating mice with leptin [53]. The expression of leptin receptor in AVPV kiss1 neuron is not observed however, in ARC it constitutes about forty two percent [53]. Insulin-like growth factor 1 (IGF-1) unlike leptin has no effects on ARC kiss1 gene but stimulates the expression of AVPV kiss1 gene [64]. In female rat, ghrelin increases the expression of ARC and AVPV kiss1gene but its receptor on kisspeptin neuron is 95

3 not reported [65]. In mice both of AVPV and ARC p a t i e n t s s u f f e r i n g f r o m kisspeptin neurons express melanocortin4 receptor idiophatichypogonadotropichypogonadism (IHH) [9, 81]. indicating some role in the regulations of kisspeptin A number of etiological factors were reported for IHH neurons [61]. such as, inactivating mutations in GnRH receptor genes, fibroblast growth factor receptor and Kal1 [82-83] but Mechanism of Action of Kisspeptin: Kisspeptin form a interestingly they account for sporadic and a subset of composite when binds to its G-protein coupled receptors, familial forms of IHH, indicating the correspondence of activating a series of cellular pathways. All this leads to other causative factors. In GPR54 gene, homozygous activations of phospholipase C (PLC-â) by releasing deletion of 155 nucleotides at the intron 4 exon 5 [81], intracellular calcium stores. After kisspeptin receptor substitution of homozygous Leu146Ser and heterozygous activations, other intracellular pathways includes mutations of X399Arg and Arg331X were responsible for accumulations of inositol-1,4,5-triphosphate, hydrolysis sporadic or familial form of IHH [9]. Similarly heterozygous of phosphatidyl inositol 4,5-bisphosphate, release of missense mutations at Arg297Leu and Cys223Arg [83] arachidonic acid and phosphorylation of extracellular and the homozygous insertion ( insC) were signal-regulated kinases 1/2 and p38 mitogen-activated reported as causative factors for IHH [84]. GPR54 gene protein kinases (MAPK) [4, 48] calcineurin and nuclear null mutations in mice were found to be a complete factor-kappa B (NF-kB) [48]. phenocopy of human patients, suggesting that GPR54 has a very indispensable role in mammalian reproduction Functions of Kisspeptin: Historically kisspeptin was [9, 85]. recognized as anti-metastatic in melanoma cells [3]. Later on, kisspeptin anti-metastatic activity was also reported CONCLUSION in the samples of thyroid cancer [66], hepatocellular cancer [67], bladder [68], stomach [69], esophagus [70], Kisspeptin regulates various physiological functions pancreatic [71], prostate [71], ovaries [72], breast [73] and in the body but most importantly it is considered as a lung cancer [74]. Kisspeptin also stimulates oxytocin central regulator of hypothalamic-pituitary-gonadal (HPG) release [4]. In placenta, kisspeptin physiologically axis. Deactivating mutation of KISS1 or KISS1R leads to regulates trophoblast invasion [44]. Kisspeptin in delay puberty, IHH and fertility problems while activating hippocampus affects neural transmission, suggesting a mutations can cause precocious puberty which in case of role in neurogenesis and epilepsy [75]. On the basis of human lead to various social and biological problems. indirect evidence, kisspeptin role as a nociception and Further, therapeutic use of the kisspeptin and its visceral regulators has been suggested [76]. In human, antagonist against a wide range of the reproductive kisspeptin and its receptors were expressed in umbilical problems is not clear. vein, aorta and coronary artery and played a role as vasoconstrictor [50]. In mouse and human heart, REFERENCES kisspeptin increases intracellular calcium concentration, operating as a cardiovascular transmitter [77]. In mouse 1. Lee, J.H., M.E. Miele, D.J. Hicks, K.K. Phillips, and human pancreas, kisspeptin enhances insulin J.M. Trent, B.E. Weissman and D.R. Welch, secretion [49]. Similarly in rats, intravenous administration KiSS-1, a novel human malignant melanoma of kisspeptin-10 increases insulin level [78]. KISS1 metastasis suppressor gene. Journal of National neurons in the hypothalamus are involved in conveying Cancer Institute, 88: metabolic information to the GnRH neurons that control 2. Horikoshi, Y., H. Matsumoto, Y. Takatsu, T. Ohtaki, reproductive axis [79]. Kisspeptin through autocrine or C. Kitada, S. Usuki and M. Fujino, Dramatical paracrine mechanisms may have a role in modulation of elevation of plasma metastin concentrations in the sympathetic function [43]. KISS1R is detected in human pregnancy: metastin as a novel placentahuman Leydig cells and also in human sperm and its direct derived hormone in humans. Journal of Clinical and intra-testicular action has been determined [80]. Endocrinology Metabolism, 88: Ohtaki, T., Y. Shintani, S. Honda, H. Matsumoto, Kisspeptin and Reproduction: The essential role of A. Hori, K. Kanehashi, Y. Terao, S. Kumano, Y. kisspeptin and GPR54 in the control of reproduction Takatsu et al., 2001 Metastasis suppressor gene evolved late in During that time, two independents KiSS-1 encodes peptide ligand of a G-proteinresearch group observed loss of function mutations in coupled receptor. Nature, 411:

4 4. Kotani, M., M. Detheux, A. Vandenbogaerde, 12. Chartrel, N., C. Dujardin, J. Leprince, L. Desrues, D. Communi, J.M. Vanderwinden, P.E. Le, S. Brezillon, M.C. Tonon, E. Cellier, T. Jouenne, G. Simonnet and R. Tyldesley, N. Suarez-Huerta, F. Vandeput, H. Vaudry, Isolation, characterization and C. Blanpain, S.N. Schiffmann, G. Vassart and distribution of a novel neuropeptide, Rana-RFamide M. Parmentier, The metastasis suppressor (R-RFa) in the brain of the European green frog gene KiSS-1 encodes kisspeptins, the natural Ranaesculenta. Journal of Comparative Neurology, ligands of the orphan G protein-coupled 448: receptor GPR54. Journal of Biological Chemistry, 13. Nelson, L.S., M.L. Rosoff and C. Li, Disruption 276: of a neuropeptide gene, flp-1, causes multiple 5. Muir, A.I., L. Chamberlain, N.A. Elshourbagy, behavioural defects in Caenorhabditiselegans. D. Michalovich, D.J. Moore, A. Calamari, Science, 281: P.G. Szekeres, H.M. Sarau, J.K. Chambers, 14. Cottrell, G.A., L.P. Schot and G.J. Dockray, P. Murdock, K. Steplewski, U. Shabon, J.E. Miller, Identification and probable role of a single neuron S.E. Middleton, J.G. Darker, C.G. Larminie, S. Wilson, containing the neuropeptide Helix FMRF-amide. D.J. Bergsma, P. Emson, R. Faull, K.L. Philpott and Nature, 304: D.C. Harrison, AXOR12, a novel human G 15. Askwith, C.C., C.C. Cheng, M. Ikuma, C. Benson, protein-coupled receptor, activated by the M.P. Price and M.J. Welsh, Neuropeptide FF peptide KiSS-1. Journal of Biological Chemistry, and FMRF amide potentiate acid-evoked currents 276: from sensory neurons and proton-gateddeg/ena C 6. Terasawa, E., K.A. Guerriero and T.M. Plant, channels. Neurons, 26: kisspeptin and puberty in mammals. In: Kauffman, AS 16. Bowman, J.W., A.R. Friedman, A.D. Thompson, and Smith, JT (eds). Kisspeptin Signaling in A.K. Ichhpurani, M.F. Kellman, N. Marks, A.G. Maule Reproductive Biology. Advance in Experimental and T.G. Geary, Structure-activity relationships Medical Biololgy, 784: of KNEFI RFamide (AF1), a nematode FMRFamide- 7. West, A., P.J. Vojta and D.R. Welch, related peptide, on Ascarissuum muscle. Peptides, Chromosome localization and genomic structure of 17: the KiSS-1 metastasis suppressor gene (KISS1). 17. Koch, G., M.L. Chen, R. Sharla and R.H. Walker, Genomics, 54: The actions of neuroactive peptides on the isolated 8. Clements, M.K, T.P. McDonald, R. Wang, G. Xie, heart of the giant African snail (Achatinafulica). B.F. O Dowd, S.R. George, C.P. Austin and Q. Liu, Comparative Biochemistry and Physiol., 106: FMRFamide-related neuropeptides are agonists 18. Lesser, W. and M.J. Greenberg, Cardiac of the orphan G-protein-coupled receptor GPR54. regulation by endogenous small cardioactive BiochemBiophys Res Commun, 284: peptides and FMRF-amide-related peptides in the 9. Seminara, S.B., S. Messager, E.E. Chatzidaki, snail Helix aspersa. Journal of Experimental Biology, R.R. Thresher, J.S. Acierno, J.K. Shagoury, Y. Bo- 178: Abbas, W. Kuohung, K.M. Schwinof, A.G. Hendrick, 19. Sakai, T., H. Satake, H. Minakata and M. Takeda, D. Zahn, J. Dixon, U.B. Kaiser, S.A. Slaugenhaupt, Characterization of crustacean cardio active J.F. Gusella, S. O Rahilly, M.B. Carlton, W.F. Crowley, peptide as a novel insect mid gut factor: S.A. Aparicio and W.H. Colledge, The GPR54 isolation, localization and stimulation of a- gene as a regulator of puberty. New England Journal amylase activity and gut contraction. Endocrinology, of Medicine, 349: : Tena-Sempere, M., Kisspeptins and the 20. Chartrel, N., F. Bruzzone, J. Leprince, H. Tollemer, metabolic control of reproduction: physiologic roles Y. Anouar, J.C. Do-Rego, I. Ségalas-Milazzo, and physiopathological implications. Annal of L. Guilhaudis, P. Cosette, T. Jouenne, G. Simonnet, Endocrinology, 71: M. Vallarino, J.C. Beauvillain, J. Costentin and 11. Dockray, G.J., The expanding family of RF H. Vaudry, Structure and functions of the novel amides peptides and their effects on feeding hypothalamic RFamide neuropeptides R-RFa and behavior. Experimental Physiology, 89(3): RFa in vertebrates. Peptides, 27:

5 21. Fukusumi, S., R. Fujii and S. Hinuma, Recent 30. Clarkson, J. and A.E. Herbison, Postnatal advances in mammalian RFamide peptides: the discovery and functional analyses of PrRP, RFRPs development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to and QRFP. Peptides, 27: gonadotropin-releasing hormone neurons. 22. Tsutsui, K., G.E. Bentley, L.J. Kriegsfeld, T. Osugi, J.Y. Seong and H. Vaudry, Discovery and evolutionary history of gonadotrophin-inhibitory hormone and kisspeptin: new key neuropeptides Endocrinology, 147: Clarkson, J., X.D. detassigny, W.H. Colledge, A. Caraty and A.E. Herbison, 2009 Distribution of kisspeptin neurones in the adult female mouse brain. controlling reproduction. Journal of Journal of Neuroendocrinology, 21: Neuroendocrinology, 22: Lee, D.K., T. Nguyen, G.P. O'Neill, R. Cheng, Y. Liu, A.D. Howard, N. Coulombe, C.P. Tan, A.T. Tang- Nguyen, S.R. George and B.F. O'Dowd, Discovery of a receptor related to the galanin 32. Adachi, S., S. Yamada, Y. Takatsu, H. Matsui, M. Kinoshita, K. Takase, H. Matsui and K. Maeda, Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in receptors. FEBS Letter, 446: female rats. Journal of Reproduction and 24. Gottsch, M.L., D.K. Clifton and R.A. Steiner, Development, 53(2): From KISS1 to kisspeptins: A historical perspective 33. Kim, J., S.J. Semaan, D.K. Clifton, R.A. Steiner, and suggested nomenclature. Peptides, 30: 4-9. S. Dhamija and A.S. Kauffman, Regulation of 25. Kirby, H.R., J.M. Janet, H.C. William and Kiss1 expression by sex steroids in the amygdala of P.D. Anthony, International Union of Basic and the rat and mouse. Endocrinology, 152: Clinical Pharmacology. LXXVII. Kisspeptin receptor 34. Mason, A.O., T.J. Greives, M.A.L. Scotti, J. Levine, S. Frommeyer, E.D. Ketterson, G.E. Demas and nomenclature, distribution and functions. L.J. Kriegsfeld, Suppression of kisspeptin Pharmacology Review, 62: expression and gonadotropic axis sensitivity 26. Rometo, A.M., S.J. Krajewski, M.L. Voytko and following exposure to inhibitory day lengths in N.E. Rance, Hypertrophy and increased female Siberian hamsters. Hormone Behavior, kisspeptin gene expression in the hypothalamic 52: infundibular nucleus of postmenopausal women and 35. Bosch, M.A., C.H. Xue and O.K. Ronnekleiv, ovariectomized monkeys. Journal of Clinical Kisspeptin expression in guinea pig Endocrinology and Metabolism, 92: hypothalamus:effects of 17 beta-estradiol. Journal of 27. Hrabovszky, E., P. Ciofi, B. Vida, M.C. Horvath, Comprative Neurology, 520: E. Keller, A. Caraty, S.R. Bloom, M.A. Ghatei, 36. Ansel, L., M. Bolborea, A.H. Bentsen, P. Klosen, W.S. Dhillo, Z. Liposits and I. Kallo, The J.D. Mikkelsen and V. Simonneaux, kisspeptin system of the human hypothalamus: Differential regulation of Kiss1 expression by sexual dimorphism and relationship with melatonin and gonadal hormones in male and female gonadotropin releasing hormone and neurokininb Syrian hamsters. Journal of Biological Rhythms, neurons. European Journal of Neuroscience, 25(2): : Wakabayashi, Y., T. Nakada, K. Murata, S. Ohkura, 28. Ramaswamy, S., K.A. Guerriero, R.B. Gibbs and K. Mogi, V.M. Navarro, D.K. Clifton, Y. Mori, T.M. Plant, Structural interactions between H. Tsukamura, K. Maeda, R.A. Steiner and kisspeptin and GnRH neurons in the mediobasal H. Okamura, Neurokinin B and dynorphin A in hypothalamus of the male rhesus monkey kisspeptin neurons of the arcuate nucleus participate (Macacamulatta) as revealed by double in generation of periodic oscillation of neural activity immunofluorescence and confocal microscopy. driving pulsatile gonadotropin-releasing hormone Endocrinology, 149: Ramaswamy, S., S.B. Seminara, B. Ali, P. Ciofi, N.A. Amin and T.M. Plant, Neurokinin B stimulates GnRH release in the male monkey secretion in the goat. Journal of Neuroscience, 30: Decourt, C., Y. Tillet, A. Caraty, I. Franceschini and C. Briant, Kisspeptin immunoreactive neurons (Macaccamulatta) and is colocalized with in the equine hypothalamus interactions with GnRH kisspeptin in the arcuate nucleus. Endocrinology, 151: neuronal system. Journal of Chemical Neuroanatomy, 36:

6 39. Yeo, S.H. and A.E. Herbison, Projections of 49. Hauge-evans, A.C., C.C. Richardson, H.M. Milne, arcuate nucleus and rostral periventricular kisspeptin neurons in the adult female mouse brain. Endocrinology, 152 : Goodman, R.L., 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 and I.J. Clarke, Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology, 148: Smith, JT Kisspeptin signaling in the brain: steroid regulation in the rodent and ewe. Brain Research Review, 57: Dun, S.L., G.C. Brailoiua, A. Parsons, J. Yang, Q. Zeng, X. Chen, J.K. Chang and N.J. Duna, Metastin-like immunoreactivity in the rat medulla oblongata and spinal cord. Neuroscience Letter, 335: Porzionato, A., G. Fenu, M. Ruciñski, V. Macchi, A. Montella, M.M. Costantino, K. Ludwik and R. De Caro, KISS1and KISS1R expression in the human and rat carotid body and superior cervical ganglion. European Journal of Histochemistrey, 55: Bilban, M., N. Ghaffari-Tabrizi, E. Hintermann, S. Bauer, S. Molzer, C. Zoratti and R. Malli, Kisspeptin-10, a KiSS-1/metastin derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts. Journal of Cell Science, 117: Nakamura, Y., S. Aoki, Y. Xing, H. Sasano and W.E. Rainey, Metastin stimulates aldosterone synthesis in human adrenal cells. Reproductive Science, 14: Brown, R.E., S.A. Imran and M. Wilkinson, KiSS-1 mrna in adipose tissue is regulated by sex hormones and food intake. Journal of Molecular and Cellular Endocrinology, 281: Silvestre, R.A., E.M. Egido, R. Hernández and J. Marco, Kisspeptin-13 inhibits insulin secretion without affecting glucagon or somatostatin release: study in the perfused rat pancreas. Journal of Endocrinology, 196: Castellano, J.M., V.M. Navarro, R. Fernández- Fernández, J.P. Castaño, M.M. Malagón, E. Aguilar, C. Dieguez, P. Magni, L. Pinilla and M. Tena-Sempere, Ontogeny and mechanisms of action for the stimulatory effect of kisspeptin on gonadotropinreleasing hormone system of the rat. Molecular and Cellular Endocrinology, : M.R. Christie, SJ. Persaud and PM. Jones, A role for kisspeptin in islets function. Diabetologia, 49: Mead, J., J. Maguire, R.E. Kuc and A.P. Davenport, Kisspeptin sare novel potent vasoconstrictors in humans, with a discrete localization of their receptor, G protein-coupled receptor 54, to atherosclerosis-prone vessels. Endocrinology, 148: Lehman, M.N., L.M. Coolen and R.L. Goodman, Mini review: kisspeptin/neurokininbs/ dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology, 151: Gottsch, M.L., M.J. Cunningham, J.T. Smith, S.M. Popa, B.V. Acohido, W.F. Crowley, S. Seminara, DK. Clifton and RA. Steiner, A role of kisspeptins in the regulation of gonadotropin secretion In the mouse. Endocrinology, 145: Smith, J.T., 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. Journal of Neuroscience, 26: Ramaswamy, S., R.B. Gibbs and T.M. Plant, Studies of the localisation of kisspeptin within the pituitary of the.rhesus monkey (Macacamulatta) and the effect of kisspeptin on the release of nongonadotropic pituitary hormones. Journal of Neuroendocrinology, 21: Tariq, A.R., M. Shahab, I.J. Clarke, A. Pereira, J.T. Smith, S.H. Khan, J. Sultan, S. Javed and T. Anwar, Kiss1 and kiss1 receptor expression in the rhesus monkey testis: a possible local regulator of testicular function. Cent Eur J Biol8: Suarez, S.S, B. Marquez, T.P. Harris and J.C. Schimenti, Different regulatory systems operate in the mid piece and principal piece of the mammalian sperm flagellum. SocReprodFertilSuppl 65: BeduAddo, K., S. Costello, C. Harper, G. Machado- Oliveira, L. Lefievre, C. Ford, C. Barratt and S. Publicover, Mobilisation of stored calcium in the neck region of human sperm a mechanism for regulation of flagellar activity. International Journal of Developmental Biology, 52:

7 58. Publicover, S.J., L.C. Giojalas, M.E. Teves, G.S. de 68. Sanchez-Carbayo, M., T.J. Belbin, K. Scotlandi, Oliveira, A.A. Garcia, C.L. Barratt and C.V. Harper, Ca2+ signalling in the control of motility and guidance in mammalian sperm. Frontier Bioscience, 13: Smith, J.T., M.J. Cunningham, E.F. Rissman, D.F. Clifton and R.A. Steiner 2005 a Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 146: Smith, J.T., H.M. Dungan, E.A. Stoll, M.L. Gottsch, R.E. Braun, S.M. Eacker, D.K. Clifton and R.A. Steiner, 2005 b. Differential regulation of KiSS-1 mrna expression by sex steroids in the brain of the male mouse. Endocrinology, 146: Cravo, R.M., L.O. Margatho, S. Osborne-Lawrence, J. DonatoJr, S. Atkin, A.L. Bookout, S. Rovinsky, R. Frazão, C.E. Lee, L. Gautron, J.M. Zigman and C.F. Elias, Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience, 173: Smith, J.T., C.M. Clay, A. Caraty and I.J. Clarke, KiSS-1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season. Endocrinology, 148: Clarkson, J., S. Shamas, S. Mallinson and A.E. Herbison, Gonadal steroid induction of kisspeptin peptide expression in the rostral periventricular area of the third ventricle during postnatal development in the male mouse. Journal of Neuroendocrinology, 24: Hiney, J.K., V.K. Srivastava, M.D. Pine and D.W. Les, Insulin-like growth factor-i activates KiSS-1 gene expression in the brain of the prepubertal female rat. Endocrinology, 150: Forbes, S., X.F. Li, J. Kinsey-Jones and K. O' Byrne, Effects of ghrelin on Kisspeptin mrna expression in the hypothalamic medial preoptic area and pulsatile luteinising hormone secretion in the female rat. Neuroscience Letter, 460: Ringel, M.D., E. Hardy, V.J. Bernet, H.B. Burch, F. Schuppert, K.D. Burman and M. Saji, Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells. Journal of Clinical Endocrinology and Metabolism, 87(5): Ikeguchi, M., Y. Hirooka and N. Kaibara, Quantitative reverse transcriptase polymerase chain reaction analysis for KISS-1 and orphan ag-proteincoupled receptor (hot7t175) gene expression in hepatocellular carcinoma. Journal of Cancer Research and Clinical Oncology, 129: M. Prystowsky, N. Baldini, G. Childs and C. Cordon- Cardo, Expression profiling ofosteosarcoma cells transfected with MDR1 and NEO genes: regulation of cell adhesion, apoptosis and tumor suppression-related genes. Laboratory Investigation, 83: Dhar, D.K., H. Naora, H. Kubota, R. Maruyama, H. Yoshimura, Y. Tonomoto, M. Tachibana, T. Ono, H. Otani and N. Nagasue, Down regulation of KiSS-1 expression is responsible for tumor invasionand worse prognosis in gastric carcinoma. International Journal of Cancer, 111: Ikeguchi, M., K. Yamaguchi and N. Kaibara, Clinical significance of the loss of KISS-1 and orphan G-protein-coupled receptor (hot7t175) gene expression in esophageal squamous cell carcinoma. Clinical Cancer Research, 10: Masui, T., R. Doi, T. Mori, E. Toyoda, M. Koizumi, K. Kami, D. Ito, S.C. Peiper, J.R. Broach, S. Oishi, A. Niida, N. Fujii and M. Imamura, Metastin and its variant forms suppress migration of pancreatic cancer cells. BiochemBiophys Res Commun, 315: Zhang, S.L., Y. Yu, T. Jiang, B. Lin and H. Gao, Expression and significance of KiSS-1 and its receptor GPR54 mrna in epithelial ovarian cancer. Zhonghua Fu Chan KeZaZhi, 40: Stark, A.M., K. Tongers, N. Maass, H.M. Mehdorn and J. Held-Feindt, Reduced metastasissuppressor.gene mrna-expression inbreast cancer brain metastases. Journal of Cancer Research and Clinical Oncology, 131: Zohrabian, V.M., H. Nandu, N. Gulati, G. Khitrov, C. Zhao, A. Mohan, J. Demattia, A. Braun, K. Das, R. Murali and M. Jhanwar-Uniyal, Gene expression profiling of metastatic brain cancer. Oncology Report, 18: Arai, A.C., Y.F. Xia, E. Suzuki, M. Kessler, O. Civelli and H.P. Nothacker, Cancer metastasissuppressing peptide metastinupregulates excitatory synaptic transmission in hippocampal dentategranule cells. Journal of Neurophysiology, 94(5): Brailoiu, G.C., S.L. Dun, M. Oshawa, D. Yin, J. Yang, J.K. Chang, E. Brailoiu and N.J. Dun, KiSS-1 expression and metastin-like immunoreactivity in the rat brain. Journal of Comparative Neurology, 481:

8 77. Kirby, H., E. Mead, J. Maguire, S. Pitkin, 82. Iovane, A., C. Aumas and N. de Roux, New W.H. Colledge, X. d Anglemont de Tassigny and insights in the genetics of isolated A.P. Davenport, Kisspeptins as hypogonadotropichypogonadism. European Journal inotropicagents in human and mouse heart. Proc. of Endocrinology, 151: Physiol. Soc., 11: Semple, R.K., J.C. Achermann, J. Ellery, I.S. Farooqi, 78. Bowe, J.E., A.J. King, J.S. Kinsey-Jones, V.L. Foot, F.E. Karet, R.G. Stanhope, S. O'rahilly and X.F. Li, K.T. O Byrne, S.J. Persaud and P.M. Jones, S.A. Aparicio, Two novel missense mutations Kisspeptin stimulation of insulin secretion: in G protein coupled receptor 54 in a patient with mechanisms of action in mouse islets and rats. hypogonadotropichypogonadism. Journal of Clinical Diabetologia, 52(5): Endocrinology and Metabolism, 90: Roa, J., E. Aguilar, C. Dieguez, L. Pinilla and M. Tena- 84. Lanfranco, F., J. Gromoll, E.S. Von, E.M. Herding, Sempere, New frontiers in kisspeptin/ E. Nieschlag and M. Simoni, Role of sequence GPR54 physiology as fundamental gatekeepers of variations of the GnRH receptor and G proteinreproductive function. Frontier Neuroendocrinology, coupled receptor 54 gene in male idiopathic 29: hypogonadotropichypogonadism. European Journal 80. Irfan, S., J. Ehmcke, F. Wahab, M. Shahab and of Endocrinology, 153: S. Schlatt, Intratesticular action of 85. Funes, S., J.A. Hedrick, G. Vassileva, L. Markowitz, kisspeptin in rhesus monkey (Macacamulatta). S. Abbondanzo, A. Golovko, S. Yang, F.J. Monsma Andrologia, 46(6): and E.L. Gustafson, The KiSS-1 receptor GPR deroux, N., E. Genin, J.C. Carel, F. Matsuda, is essential for the development of the murine J.L. Chaussain and E. Milgrom, reproductive system. BiochemBiophys Res. Hypogonadotropichypogonadism due to loss of Commun., 312: function of the KiSS1-derived peptide receptor GPR54. PNAS USA, 100: