Short communicationEffect of peripherally administered kisspeptin-10 on GnRH neurosecretion into the hypophyseal portal circulation in ovariectomized goat does
Introduction
Kisspeptin (also known as metastin) was first discovered in 2001 as an endogenous ligand for the G protein-coupled receptor 54 (GPR54), with a suppressive effect on metastasis (Ohtaki et al., 2001). It was found that mutations of GPR54 were associated with hypogonadotropic hypogonadism in humans (de Roux et al., 2003, Seminara et al., 2003). These findings indicate that kisspeptin may play a critical role in reproduction. It has now been shown in a variety of mammalian species that kisspeptins (either full length or kisspeptin-10 (kp-10), the C-terminal amidated 10-amino-acid sequence of kisspeptin) act as potent LH secretagogues (Matsui et al., 2004, Messager et al., 2005, Ohkura et al., 2009b). Central administration of an antibody against kisspeptin in rats (Kinoshita et al., 2005), or the GPR54 antagonist in several species (Roseweir et al., 2009) inhibited LH secretion. Moreover, evidence suggests that their actions on LH secretion are mediated by GnRH. The kisspeptin-induced LH release was blocked by a pre-treatment with a GnRH antagonist in rodents (Matsui et al., 2004) and primates (Shahab et al., 2005).
In the course of the study to clarify the involvement of kisspeptin in the regulation of GnRH and LH secretion, it became experimentally important to determine the effect of kisspeptin on GnRH secretion in goats. Direct measurement of GnRH in vivo, after kisspeptin treatment, has been reported in sheep (Messager et al., 2005, Smith et al., 2011) and rhesus monkeys (Keen et al., 2008). However, a recent electrophysiological study on goats demonstrated that kp-10 stimulates LH secretion, without the promotion of periodic bursts of the hypothalamic multiple unit activity, that are synchronized with the pulsatile release of LH (Ohkura et al., 2009a). It suggests that the hypothalamic neural generator governing the pulsatile GnRH secretion is not directly related to the kp-10-induced LH release in goats. Moreover, it is possible that kisspeptin modulates LH secretion at the pituitary level in other species. In vitro studies demonstrated that kp-10 treatment stimulated LH secretion from the anterior pituitary cells in the bovine (Ezzat et al., 2010) and porcine (Suzuki et al., 2008) species. Therefore, in the present study, the effect of intravenous administration of kp-10 on GnRH concentrations in the hypophyseal portal circulation in ovariectomized goats was investigated.
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Materials and methods
Long-term (>3 months) ovariectomized Shiba goat does (4–8 years of age, n = 3) were used. The procedure for implantation of the apparatus for collection of portal blood was as previously described (Tanaka et al., 1997). Briefly, the collection apparatus (90–100 mm length) was surgically implanted at the front of the anterior face of the pituitary, through the sphenoid bone with the aid of an operating microscope (KOM330CA, Konan Medical Inc., Nishinomiya, Japan). After the surgery, the goats were
Results
The secretory patterns of GnRH in the hypophyseal portal circulation and of LH in the peripheral circulation of the 3 ovariectomized goats are shown in Fig. 1. In all animals, the plasma concentration of GnRH and LH increased immediately after the kp-10 administration. A significant increase (p < 0.05) in the percentage changes in the AUC of GnRH concentrations during the 30-min periods, relative to total AUC of GnRH, was detected only in the period from 0 to 0.5 h (32.8 ± 24.4%) after kp-10
Discussion
The present study demonstrated that kisspeptin directly stimulated GnRH neurosecretion into the hypophyseal portal circulation, accompanied by increases in the peripheral concentrations of LH in goats – supporting previous studies in other species, that kp-10 has the potency for inducing GnRH release in vivo (Messager et al., 2005, Keen et al., 2008, Smith et al., 2011). A majority of the GnRH neurons express GPR54 (Irwig et al., 2004, Han et al., 2005), and peripheral administration of
Acknowledgments
Thanks to Dr. A. Caraty, Institut National de la Recherche Agronomique, Nouzilly, France, for providing reagents used in the GnRH RIA, Dr. Y. Mori, The University of Tokyo, Japan, for providing anti-ovine LH serum (YM #18), and Dr. A.F. Parlow and the National Hormone & Peptide Program, USA, for reagents used in the LH RIA. This study was supported in part by the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) of Japan.
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