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

World Journal of Zoology 10 (2): 94-101, 2015 ISSN 1817-3098 IDOSI Publications, 2015 DOI: 10.5829/idosi.wjz.2015.10.2.9387 Kisspeptin, its Localization and Physiological Functions in Primates: A Review 1 2 3 4 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: +92 345 8112741. 94

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

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 (1001 1002insC) 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, 1996. 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: 1731-1737. 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, 2003. 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: 914-919. 3. 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 2003. 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: 613-617. 96

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