Abstract
Kisspeptins (Kps) have emerged as key players in the control of reproductive-axis function, in which they operate as primary regulators of hypothalamic GnRH release. 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 and GH release 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 Ca(2+) mobilization, but not adenylyl cyclase, protein kinase A, extracellular Ca(2+) 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.
Highlights
Kisspeptins (Kps) have emerged as key players in the control of reproductive-axis function, in which they operate as primary regulators of hypothalamic GnRH release
In mammals, a prominent population of Kiss1 neurons has been demonstrated in the arcuate nucleus in both sexes [4, 5]. In rodents another group of kisspeptin neurons are located in the anteroventral periventricular (AVPV) nucleus and adjacent areas, in which this neuronal population seems to be more abundant in females [4, 5]
Kp-10, GnRH, GHRH, ghrelin, and SST were purchased from Sigma and Phoenix Pharmaceuticals (Burlingame, CA). ␣-MEM, HEPES, horse serum, and penicillin-streptomycin were obtained from Invitrogen (Grand Island, NY)
Summary
Kisspeptins (Kps) have emerged as key players in the control of reproductive-axis function, in which they operate as primary regulators of hypothalamic GnRH release. Kisspeptin and GnRH axons have been found in close association within the median eminence of monkeys [7] These findings, coupled with an abundance of convincing functional data, have led to the notion that Kiss neurons within the hypothalamus are pivotal afferents in the circuitry governing GnRH secretion, in which they operate as major nodal points for the integration and transmission of key regulatory signals, from sex steroids to metabolic hormones [3]. Expression of Kiss and Kiss1r mRNAs has been documented in the pituitary of rats, sheep, and humans under the control of GnRH and/or sex steroids (14 –17) These data suggest a plausible functional role of Kp signaling at the pituitary level. Evidence suggests that the pituitary actions of Kps might involve the modulation of other neuroendocrine axes, such as the somatotroph system [9, 10, 20, 21], but this action remains controversial
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