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

Abstract

The gonadotropic axis is centrally controlled by a complex regulatory network of excitatory and inhibitory signals that is activated at puberty. Recently, loss of function mutations of the gene encoding G protein-coupled receptor 54 (GPR54), the putative receptor for the KiSS-1-derived peptide metastin, have been associated with lack of puberty onset and hypogonadotropic hypogonadism. Yet the pattern of expression and functional role of the KiSS-1/GPR54 system in the rat hypothalamus remain unexplored to date. In the present work, expression analyses of KiSS-1 and GPR54 genes were conducted in different physiological and experimental settings, and the effects of central administration of KiSS-1 peptide on LH release were assessed in vivo. Persistent expression of KiSS-1 and GPR54 mRNAs was detected in rat hypothalamus throughout postnatal development, with maximum expression levels at puberty in both male and female rats. Hypothalamic expression of KiSS-1 and GPR54 genes changed throughout the estrous cycle and was significantly increased after gonadectomy, a rise that was prevented by sex steroid replacement both in males and females. Moreover, hypothalamic expression of the KiSS-1 gene was sensitive to neonatal imprinting by estrogen. From a functional standpoint, intracerebroventricular administration of KiSS-1 peptide induced a dramatic increase in serum LH levels in prepubertal male and female rats as well as in adult animals. In conclusion, we provide novel evidence of the developmental and hormonally regulated expression of KiSS-1 and GPR54 mRNAs in rat hypothalamus and the ability of KiSS-1 peptide to potently stimulate LH secretion in vivo. Our current data support the contention that the hypothalamic KiSS-1/GPR54 system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood.

Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling

“…Similar observations (but with higher doses of kisspeptin) were reported in the rat (Matsui et al 2004, Navarro et al 2004a, sheep (Messager et al 2005), monkey (Shahab et al 2005, Plant et al 2006 and, most recently, the human male (Dhillo et al 2005). In addition to corroborating the observation that kisspeptin stimulates gonadotropin secretion, these latter studies also demonstrated that the effect of kisspeptin on circulating levels of LH is unusually prolonged -far beyond that which would have been produced by centrally administered secretagogues, such as N-methyl-D-aspartate (NMDA) (Saitoh et al 1991, Navarro et al 2004a. Moreover, as demonstrated in the mouse, rat, and monkey, the GnRH antagonist acyline can block the kisspeptin-induced release of LH and FSH , Irwig et al 2004, Shahab et al 2005.…”

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

“…Significant research shows that expression of KiSS-1 and GPR54 are sexually dimorphic, with most studies focusing on the AVPV as a key control center of the preovulatory GnRH/LH surge, and the arcuate nucleus as a potential target for negative feedback of the hypothalamic-pituitarygonadal axis by steroid hormones [147]. In the context of neural imprinting, when newborn male pups were given a single injection of estradiol on day 1, and hypothalamic gene expression was measured in adulthood at day 60, there was a significant decrease in KiSS-1 mRNA and serum LH, although GnRH and GPR54 mRNA did not differ from controls [105]. Although these data merit further investigation, they implicate the kisspeptin system as part of the imprinted hypothalamic network that controls reproductive neuroendocrine function.…”

Caloric restriction: Impact upon pituitary function and reproduction

“…Interestingly, these Kiss neurons are thought to be the primary manner in which hypothalamic neuronal inputs are relayed to the GnRH neurons, which do not appear to express many of the necessary receptors that are required for the induction of the appropriate responses to hormones and factors such as leptin, ghrelin, dopamine, estradiol, and other factors that are related to the nutritional status of the organism (Dungan et al, 2006;Maeda et al, 2007). The activation of Kiss1 gene expression is likely to play an important role in timing the onset of puberty, sexual differentiation of the GnRH/LH surge mechanism, and the preovulatory GnRH/LH surge itself (in females) (Gottsch et al, 2004a;Shahab et al, 2005;Han et al, 2005, Navarro et al, 2004.…”