Characterization of the inhibitory roles of RFRP3, the mammalian ortholog of GnIH, in the control of gonadotropin secretion in the rat: in vivo and in vitro studies

Abstract

van Noort PI, Tena-Sempere M. Characterization of the inhibitory roles of RFRP3, the mammalian ortholog of GnIH, in the control of gonadotropin secretion in the rat: in vivo and in vitro studies. Am J Physiol Endocrinol Metab 299: E39 -E46, 2010. First published April 27, 2010; doi:10.1152/ajpendo.00108.2010.-RF-amide related peptides (RFRP), as putative mammalian orthologs of the avian gonadotropin-inhibitory hormone (GnIH), have been proposed as key regulators of gonadotropin secretion in higher vertebrates. Yet considerable debate has arisen recently on their physiological relevance and potential mechanisms and sites of action. Present studies were undertaken to further characterize the effects of RFRP on LH and FSH secretion by a combination of in vivo and in vitro approaches in male and female rats. Initial screening via intracerebroventricular (icv) administration of different analogs of RFRP1 (RFRP1-12 and RFRP1-20) and RFRP3 (RFRP3-8 and RFRP3-17), as well as the related neuropeptide FF (NPFF8), to gonadectomized (GNX) female rats evidenced significant, albeit modest, inhibitory effects on LH secretion only for RFRP3-8 and RFRP3-17, which were detectable at the high dose rage (1 nmol for RFRP3-8, 5 nmol for RFRP3-17). This moderate inhibitory action was also documented after icv administration of RFRP3-8 to intact and GNX male rats. In addition, systemic (intravenous) administration of RFRP3-8 decreased the circulating levels of both gonadotropins in GNX male rats. Likewise, RFRP3-8 inhibited basal and GnRH-stimulated LH secretion by pituitaries from GNX males in vitro. This inhibitory effect was blocked by the antagonist of RFRP receptors, RF9. In summary, our results support a putative inhibitory role of RFRP3 as ortholog of GnIH in the regulation of gonadotropin secretion in mammals, which appears to involve direct pituitary actions as well as potential central (hypothalamic) effects.RF-amide related peptide; gonadotropin-inhibitory hormone; gonadotropin-releasing hormone; neuropeptide FF; receptor; RF9 THE NEUROENDOCRINE CONTROL of the gonadotropic axis relies on a complex array of stimulatory and inhibitory signals that primarily, but not exclusively, impinge onto a subset of hypothalamic neurons producing the decapeptide gonadotropinreleasing hormone (GnRH) (7, 15). Our knowledge on the nature and mechanisms of action of these neuroendocrine regulators has enlarged considerably recently, with the identification of novel factors (e.g., kisspeptins) and unsuspected biological effects of classical signals (e.g., excitatory actions of putative inhibitory neurotransmitters such as GABA) (7,22). In this context, a 12-amino acid neuropeptide, with a distinctive RF-amide (RFa) motif at its COOH terminus, was isolated from the avian brain in 2000 and termed gonadotropin-inhibitory hormone (GnIH) due to its capacity to suppress gonadotropin release by quail pituitaries (30). This finding boosted a considerable interest in the field, as this was thought to represent the physiological counterpart of GnRH or on...

Gonadotropin-Inhibitory Hormone Is a Hypothalamic Peptide That Provides a Molecular Switch between Reproduction and Feeding

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How to contribute to the progress of neuroendocrinology: New insights from discovering novel neuropeptides and neurosteroids regulating pituitary and brain functions

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“…In addition to its hypothalamic expression, GnIHR expression has been reported in the pituitary (Ubuka et al 2009b) and the gonads (McGuire & Bentley 2010). The inhibitory effect of GnIH on reproductive hormones secretion can be blocked by the GnIHR antagonist RF9 (Pineda et al 2010a,b, Rizwan et al 2012.…”