Characterization of the Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide, the Natural Ligand of GPR54

Abstract

Loss-of-function mutations of the gene encoding GPR54, the putative receptor for the KiSS-1-derived peptide metastin, have been recently associated with hypogonadotropic hypogonadism, in both rodents and humans. Yet the actual role of the KiSS-1/GPR54 system in the neuroendocrine control of gonadotropin secretion remains largely unexplored. To initiate such analysis, the effects of KiSS-1 peptide on LH secretion were monitored using in vivo and in vitro settings under different experimental conditions. Central intracerebroventricular administration of KiSS-1 peptide potently elicited LH secretion in vivo over a range of doses from 10 pmol to 1 nmol. The effect of centrally injected KiSS-1 appeared to be mediated via the hypothalamic LHRH. However, no effect of central administration of KiSS-1 was detected on relative LHRH mRNA levels. Likewise, systemic (i.p. and i.v.) injection of KiSS-1 markedly stimulated LH secretion. This effect was similar in terms of maximum response to that of central administration of KiSS-1 and might be partially attributed to its ability to stimulate LH secretion directly at the pituitary. Finally, the LH-releasing activity of KiSS-1 was persistently observed after blockade of endogenous excitatory amino acid and nitric oxide pathways, i.e. relevant neurotransmitters in the neuroendocrine control of LH secretion. In summary, our results provide solid evidence for a potent stimulatory effect of KiSS-1 on LH release, acting at central levels (likely the hypothalamus) and eventually at the pituitary, and further document a novel role of the KiSS-1/GPR54 system as a relevant downstream element in the neuroendocrine network governing LH secretion.

Expression of Hypothalamic KiSS-1 System and Rescue of Defective Gonadotropic Responses by Kisspeptin in Streptozotocin-Induced Diabetic Male Rats

“…For hormonal tests, a protocol of intracerebral injection of kisspeptin-10 was applied to control and STZinjected animals. To allow delivery of kisspeptin into the lateral cerebral ventricle, the animals were implanted under ether anesthesia with intracerebroventricular cannulae lowered to a depth of 3 mm beneath the surface of the skull; the insert point was 1 mm posterior and 1.2 mm lateral to bregma, as described previously (22,29,31). Two doses of kisspeptin-10 were tested: 1 nmol (maximal) and 10 pmol (submaximal) in 10 l. Blood samples (300 l) were obtained by jugular venipuncture under light ether anesthesia before (0 min) and at 15 and 60 min after kisspeptin injection.…”

“…These findings drew immediate attention to the previously unsuspected neuroendocrine facet of kisspeptins, ligands of GPR54, which are structurally related peptides generated by the differential proteolytic processing of a common precursor encoded by the metastasis suppressor KiSS-1 gene (19 -21). Indeed, a wealth of data has now demonstrated that kisspeptins are potent elicitors of the GnRH/gonadotropin axis in a number of species, including humans (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), and mechanistic studies have suggested a relevant role of KiSS-1 signaling in puberty onset in rodents and primates (24,27). Moreover, hypothalamic expression of the KiSS-1 gene appeared to be maximal at puberty and regulated by sex steroids (22)(23)(24)(25)(26).…”

Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling

“…The apparent lack of kisspeptin's effect on the pituitary was confirmed in the rat by Matsui et al (2004), who reported that another GnRH antagonist, cetrorelix, also blocks the kisspeptin-induced release of LH and FSH. However, in vitro, kisspeptin has been shown to stimulate LH release and augment GnRH-stimulated FSH release from pituitary explants derived from peripubertal male rats -albeit modestly (Navarro et al 2005a(Navarro et al , 2005b; nevertheless, kisspeptin has little or no effect on the release of either LH or FSH from primary cultures of pituitary cells derived from rats (Matsui et al 2004). Moreover, another study reports that kisspeptin has no effect on LH and FSH release from rat pituitary explants, yet it stimulates GnRH secretion from hypothalamic explants (Thompson et al 2004).…”

Atrazine-induced elevation or attenuation of the LH surge in the ovariectomized, estrogen-primed female rat: role of adrenal progesterone

“…Kisspeptin (Kiss1) neurons in the hypothalamic anteroventral periventricular nucleus (AVPV) send fibers to GnRH neurons, and it has become apparent that this input serves as a powerful impetus for elicitation of the LH surge (e.g. Gottsch et al 2004, Navarro et al 2005. This study examined the relationship between the expression of Kiss1 mRNA in the AVPV and the surge following 1 and 4 days of ATRZ exposure.…”