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Kisspeptin Regulates Gonadotroph and Somatotroph Function in Nonhuman Primate Pituitary via Common and Distinct Signaling Mechanisms

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posted on 14.08.2012 by Rau´ l M. Luque, Jose´ Co´ rdoba-Chaco´ n, Manuel D. Gahete, Víctor M. Navarro, Manuel Tena-Sempere, Rhonda D. Kineman, Justo P. Castan˜ o
Kisspeptins (Kps) have emerged as key players in the control of reproductive-axis function, in which they operate as primary regulators of hypothalamicGnRHrelease. In addition, recent data indicate that Kps can also directly act on the pituitary to stimulate LH and GH release in primary pituitary cell culture prepared from rats, cows, and sheep. We present herein evidence that Kps (specifically Kp-10) can also stimulate LH andGHrelease in primary pituitary cell cultures prepared from female baboons (Papio anubis), a species that more closely models human physiology. The stimulatory effect of Kp-10 on LH and GH release was dose and time dependent and enhanced the hormonal responses to their major regulators (GnRH for LH; GHRH/ghrelin for GH) without affecting the release of other pituitary hormones (TSH, FSH, ACTH, prolactin). Use of pharmacological intracellular signaling blockers indicated Kp-10 signals through phospholipase C, protein kinase C, MAPK, and intracellular Ca2 mobilization, but not adenylyl cyclase, protein kinase A, extracellular Ca2 influx (through L-type channels), or nitric oxide synthase, to stimulate both LH and GH release. Interestingly, blockade of mammalian target of rapamycin or phosphoinositol 3-kinase activity fully abolished the stimulatory effect of Kp-10 on LH but not GH release. Of note, estradiol enhanced the relative LH response to Kp-10, alone or in combination with GnRH. In sum, our data are the first to provide evidence that, in a primate model, there is a functional Kp-signaling system within the pituitary, which is dynamically regulated and may contribute to the direct control of gonadotropic and somatotropic axes. (Endocrinology 152: 957–966, 2011)




This work was supported by Grants RYC-2007-00186, JC2008-00220, BFU2008-01136/BFI (to R.M.L.), FI06/00804 (to J.C.-C.), and FPU-AP20052473 (to M.D.G.); 7th European Union Marie Curie Fellowship Program (to V.M.N.); BFU 2008- 00984/BFI (to M.T.-S.); National Institute of Diabetes and Digestive and Kidney Diseases Grant 30677; Veterans Affairs Merit Award (to R.D.K.) and Grants BFU2007-60180/BFI, FIG. 4. Interaction of Kp-10 (10 nM) with regulators of gonadotrope and somatotrope function in the absence or presence of estradiol (E2 or E2, respectively; 10 nM) in primary pituitary cell cultures from baboons. A, Effect of 4 h treatment of Kp and/or GnRH (10 nM) on LH secretion. B, Effect of 4 h treatment of Kp and/or GHRH, ghrelin (10 nM), or SST (100 nM) on GH secretion. Data are expressed as percentage of controls without E2 (set at 100%), and represent the mean SEM of three to four independent experiments (three to four wells per experiment). Values that do not share a common letter (a, b, c, d) are statistically different. Asterisks indicate values that significantly differ from their respective control values (same treatment in the absence of estradiol). *, P 0.05; **, P 0.01. 964 Luque et al. Kisspeptin Signaling at the Primate Pituitary Endocrinology, March 2011, 152(3):957–966 BFU2010-19300, BIO-139, CTS-1705, and CTS-5051; and grants from IPSEN Pharmaceuticals, Milford, MA (to J.P.C.). Centro de Investigacio´n Biome´dica en Red is an initiative of the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacio´n, Spain.


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The original version is available through Endocrine Society at DOI: 10.1210/en.2010-1142


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