Hipotalamo–Hipofizer-Gonadal Aks’ta Kisspeptin’in Fizyolojik Rolü

Nörohormonal sistemde, memeli üreme aksı üç temel doku ve bölümün birleşmesiyle düzenlenir; bunlar hipotalamus, hipofiz ve gonadlardır. Dişilerde, hipotalamo-hipofizer-gonadal (HPG) aksın temel fizyolojik fonksiyonu reproduktif faaliyetlerin devamı ve performans için gerekli hormonların salgılanmasını, ovumun elde edilmesini, gebeliğin oluşumunu ve sağlıklı gebeliğin devamını sağlamaktır. Bu üçlü aksın hipotalamus kısmını gonadotropin serbestleyici hormon (GnRH), hipofiz kısmını follikül uyarıcı (FSH) ve lüteinleştirici (LH) hormonlar, ovaryum kısmını ise östrojen ve progesteron oluşturmaktadır. Klasik bilgi olarak hipotalamustan GnRH salınmakta, hipotalamo-hipofizer portal dolaşımla yüksek yoğunlukta ön hipofizdeki reseptörler aracılığı ile gonodrop hücreleri uyarmakta ve bu hücrelerden FSH ve LH salgılanmaktadır. Folikül uyarıcı hormon, ovaryumda follikül gelişimini ve östrojen hormonunun salınımını uyarırken, LH ise ovulasyonu gerçekleşmektedir. Hipotalamus, hipofiz ve gonadal aks da GnRH-FSH/LH-östrojen/progesteron yolu bir çok memeli türünde iyi tanımlanmış olmasına rağmen ön beyindeki bu işlevi başlatan moleküler ve hücresel olaylar henüz tam olarak bilinmemektedir. Fakat son yıllarda kisspeptinin keşfedilmesi, başta GnRH salınım olmak üzere, puberta ve üremenin metabolik düzenlenmesinde birçok bilinmeyenin ortaya çıkmasına neden olmuştur. Kisspeptinler, peptit bir aileden oluşan ve Kiss 1 gen tarafından kodlanarak G protein-coupled receptor (GPR54)’e bağlanan hormonlardır. İnsanlarda ve farelerde GPR54 mutasyonlarındaki eksiklik ya da yetersizlikler hipogonadotropik hipogonadizmle sonuçlanmıştır. Bu da kisspeptinlerin GnRH sekresyonu düzenlemesinde hayati bir rol üstlendiğini göstermektedir. Kisspeptinlerin pubertenin zamanlanması ve HPG aks regülasyonunda etkili oldukları bilinmekle birlikte üremenin nöronal kontrolü açısından açıklığa kavuşturulmayı bekleyen pek çok nokta bulunmaktadır. Bu derlemenin amacı, kisspeptinlerin yapısı, nöronal kontrolü hakkındaki bilgilere katkı sağlayarak, üreme ve sinir sistemindeki rolleri açısından kisspeptinlerin önemine dikkati çekmek ve ileride yapılması planlanabilecek çalışmalara ışık tutmaktır.

Anahtar Kelimeler:

Kisspeptin, GPR54, GnRH, FSH, LH, Puberta

Physiogical Role of Kisspeptin in The Hypothalamic-Pituitary-Gonadal Axis

In neurohormonal system, mammalian reproductive axis is regulated by combination of three fundamental tissues and parts; these are hypothalamus, hypophysis and gonads. Females, the main physiological function of the hypothalamic-pituitary-gonadal axis (HPG) in the reproductive performance of activities required for continued secretion of hormones, ovum acquisition, to ensure continuation of pregnancy with the formation of a healthy pregnancy. This is part of a triple hypothalamic gonadotropin axis releasing hormone (GnRH), pituitary follicle-stimulating hormone (FSH) and luteinizing hormones (LH), estrogen and progesterone in the ovary is the part. Classical information is released from the hypothalamus, GnRH, pituitary receptors in the hypothalamic-pituitary portal circulation through the front of the high-density gonodrop cells and stimulates FSH and LH are secreted from these cells. Follicle-stimulating hormone, stimutales the release of ovarian follicle development and estrogen hormone, ovulation takes place in the LH. The hypothalamus, pituitary and gonadal axis GnRH-FSH/LH-estrogen/progesterone way to the front of many mammalian species, although well-defined molecular and cellular events that started in the brain function is not fully understood yet. But in recent years the discovery of kisspeptin, particularly in GnRH secretion, puberta and metabolic regulation of reproduction has resulted in many of the unknown. The Kiss1 gene encodes a family of peptides called kisspeptins, which are the natural ligands for the receptor G protein-coupled receptor (GPR54). In humans and mice, inactivating mutations of GPR54 results in hypogonadotropic hypogonadism, indicating that kisspeptins play a vital role in the regulation of GnRH secretion. Many aspects of the roles of kisspeptins on the neuroendocrine regulation of reproduction are still not clear, despite the knowledge of their regulatory effects on timing puberty and hypothalamic-pituitary-gonadal axis. The aim of this review, to contribute our knowledge about structure of the kisspeptins, neuronal control and draw attention the importance role kisspeptins of in reproductive and nervous system and shed light on future studies.

Keywords:

Kisspeptin, GPR54, GnRH, FSH, LH, Puberty,

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Aparicio S (2005). Kisspeptins and GPR54 - The new biology of the mammalian GnRH axis. Cell Metab, 1, (5), 293-6. Castellano JM, Navarro VM, Fernández-Fernández R, Roa J, Vigo E, Pineda R, et al. (2006). Expression of hypothalamic KISS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-ınduced diabetic male rats. Diabetes, 55, (9), 2602-2610. Clarke J, Smith JT, Caraty A, Robert L, Goodman RL, Michael N, et al. (2009). Kisspeptin and seasonality in sheep. Peptides, 30, (1),154–163. Colledge WH (2004). GPR54 and puberty. Trends Endocrinol Metab, 15, (9),448-453. De Tassigny XDA, & Colledge WH (2010). The role of kisspeptin signaling in reproduction. Physiology, 25, (4), 207-217. Dubois SL, Acosta-Martínez M, DeJoseph MR, Wolfe A, Radovick S, Boehm U, et al. (2014). Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in Kisspeptin neurons. Endocrinology, 156, (3),1111-1120. Durmaz A, Dikmen N (2007). The chemical kiss: Kisspeptin. Archives Medical Review Journal, 16, (3),172-184. Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, et al. (2003). The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biop Res Co, 312, (4),1357-1363. Gottsch ML, Clifton DK, Steiner RA (2006). Kisspeptin-GPR54 signaling in the neuroendocrine reproductive axis. Mol Cell Endocrinol, 254, 91-96. Greives TJ, Mason AO, Scotti MAL, Levine J, Ketterson ED, Kriegsfeld LJ, et al. (2007). Environmental control of Kisspeptin: implications for seasonal reproduction. Endocrinology, 148, 1158–1166. Grumbach MM (2002). The neuroendocrinology of human puberty revisited. Horm Res Paediatr, 57, (2),2-14. Jeremy TS (2008). Kisspeptin signaling in the brain: steroid regulation in the rodent and ewe. Brain Res Rev, 57, (2),288-298. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Poul EL, et al. (2001). The metastasis suppressor gene KiSS-1 encodes Kisspeptins, the natural ligands of the orphan g protein-coupled receptor GPR54. J Biol Chem, 276, (37), 34631-3436. Kriegsfeld LJ (2007). Driving reproduction: RF amide peptides behind the wheel. Horm Behav, 52, (4),492-498. Kuohung W, Kaiser UB (2006). GPR54 and KiSS-1: Role in the regulation of puberty and reproduction. Rev Endocr Metab Dis, 7, (4),257-263. Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, et al. (1996). KiSS-1, a noval human malignant melanoma metastasis-suppressor gene. J Natl Cancer I, 88, (23),1731-1771. Lee JH, Welch DR (1997). Identification of highly expressed gene in metastasis-suppressed chromosome 6/human malignant melanoma hybrid cells using subtractive hybridization and differential display. Int J Cancer, 71, (6), 1035-1041. Lents CA, Heidorn NL, Barb CR, Ford JJ (2008). Central and peripheral administration of kisspeptin activates gonadotropin but not somatotropin secretion in pubertal gilts. Reproduction, 135, (6), 879-887. Liu X, Herbison A (2015). Kisspeptin regulation of arcuate neuron excitability in Kisspeptin receptor knockout mice. Endocrinology, 156, (5),1815-1827. Magee C, Arreguin-Arevalo A, Bruemmer J, Mrdutt M, Cantlon J, McCue P, et al. (2008). Peripheral Kisspeptide administration elicits an ıncrease in serum FSH in the diestrous mare. Biol Reprod, 78, (1), 220-221. Magee C, Foradori CD, Bruemmer JE, Arreguin-Arevalo JA, McCue PM, Handa RJ, et al. (2009). Biological and anatomical evidence for Kisspeptin regulation of the hypotalmic-pituitary-gonadal axis of estrous horse mares. Endocrinology, 150, (6),2813-2821. Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, et al. (2004). 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, (10),4565-4574. Sarvestani FS, Tamadon A, Koohi-Hosseinabadi O, Nezhad SM, Rahmanifar F, Shirazi MRJ, et al. (2014). Expression of RFamide-related peptide-3 (RFRP-3) mRNA in dorsomedial hypothalamic nucleus and KiSS-1 mRNA in arcuate nucleus of rat during pregnancy. Int J Fertil & Steril, 8, (3),333-340. Scott CJ, Setterfield CA, Coraty A, Norman ST (2010). Is there variation in the level of input of Kisspeptin terminals onto GNRH neurons across the equıne oestrous. Reproduction, 22, 129-130. Sebert ME, Lomet D, Said SB, Monget P, Briant C, Scaramuzzi RJ, et al. (2010). Insights into the mechanism by which Kisspeptin stimulated a preovulatory LH surge and ovulation in seasonally acyclic ewes: potential role of estradiol. Domest Anim Endocrin, 38, (4),289-298. Seminara SB (2005). Metastin and its G protein-coupled receptor, GPR54: critical pathway modulating GnRH secretion. Front Neuroendocrin, 26, (3),131-138. Skorupskaite K, George JT, & Anderson RA (2014). The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update, 20(4), 485-500. Smith JT, Acohido BV, Clifton DK, Steiner RA (2006). Kiss-1 neurons are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol, 18(4):298-303. Taskiran N (2014). Determination of the effects of Melatonin/Kisspeptin interaction in female rats in prepubertal period on puberty age and hormones tasked with ovulation. Afyon Kocatepe University Graduate Schooll of Medical Sciences, Departman of Physiology, PhD Thesis, Turkey. Tena-Sempere M (2006). GPR54 and Kisspeptin in reproduction. Hum Reprod Update, 12, (5),631-639. Terao Y, Kumano S, Takatsu Y, Hattori M, Nishimura A, Ohtaki T, et al. (2004). Expression of KiSS-1, a metastasis suppressor gene, in trophoblast giant cells of the rat placenta. BBA-Gene Struct Expr, 1678, (2),102-110. Terasawa E, Fernandez DL (2001). Neurobiological mechanisms of the onset of puberty in primates 1. Endocr Rev, 22, (1),111-151. Toporikova N, Dishuck P, Tabak J, Helena C (2014). Kisspeptin mediation of estradiol-induced secretion of luteinizing hormone and prolactin. BMC Neurosci, 15, (1),147-148. Whitlock BK, Daniel JA, Wilborn RR, Maxwell HS, Steele BP, Sartin JL. (2010). Interaction of Kisspeptin and the somatotropic axis. Neuroendocrinology, 92, (3),178-188.