KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis

Abstract

Kisspeptin (KP) is now well recognized as a potent stimulator of gonadotropin-releasing hormone (GnRH) secretion and thereby a major regulator of the neuroendocrine-reproductive axis. KP signals via KISS1R, a G protein-coupled receptor (GPCR) that activates the G proteins Gα_q/11. Modulation of the interaction of KP with KISS1R is therefore a potential new therapeutic target for stimulating (in infertility) or inhibiting (in hormone-dependent diseases) the reproductive hormone cascade. Major efforts are underway to target KISS1R in the treatment of sex steroid hormone-dependent disorders and to stimulate endogenous hormonal responses along the neuroendocrine axis as part of in vitro fertilization protocols. The development of analogs modulating KISS1R signaling will be aided by an understanding of the intracellular pathways and dynamics of KISS1R signaling under normal and pathological conditions. This review focuses on KISS1R recruitment of intracellular signaling (Gα_q/11- and β-arrestin-dependent) pathways that mediate GnRH secretion and the respective roles of rapid desensitization, internalization, and recycling of resensitized receptors in maintaining an active population of KISS1R at the cell surface to facilitate prolonged KP signaling. Additionally, this review summarizes and discusses the major findings of an array of studies examining the desensitization of KP signaling in man, domestic and laboratory animals. This discussion highlights the major effects of ligand efficacy and concentration and the physiological, developmental, and metabolic status of the organism on KP signaling. Finally, the potential for the utilization of KP and analogs in stimulating and inhibiting the reproductive hormone cascade as an alternative to targeting the downstream GnRH receptor is discussed.

Multiple failures in the lutenising hormone surge generating system in GABAB1KO female mice

“…Nevertheless, overall increased GnRH secretion mass per pulse was observed in GABAB1KO hypothalamus, suggesting that increased Kiss1r mRNA expression may have induced increased GnRH secretion. Under these conditions, the Kiss1r antagonist Kiss‐234 inhibited GnRH secretion in both genotypes, without altering pulse frequency, and this was partly reversed by the co‐administration of Kiss‐10, demonstrating that the hypothalamus was responsive to constant kisspeptin, as also suggested by Young et al Indeed, there is conflicting information regarding the desensitisation of kisspeptin receptors under chronic kisspeptin stimulation, with some studies showing desensitisation of the GnRH response, whereas others show persistency of this response, and these differences may depend on ligand efficacy, circulating levels of gonadal steroids and metabolic status.…”

“…To better mimic physiological conditions before the onset of the kisspeptin surge, in which oestradiol levels are high and in which kisspeptin is secreted in pulsatile fashion, hypothalamus from OVX‐E 2 ‐VAL‐treated mice was incubated ex vivo with or without constant E 2 in the incubation medium, and stimulated with pulsatile Kiss‐10 (one pulse per hour). In this setting, and in contrast to the previous one, no effects were observed on GnRH secretion pulse mass by any treatment in any genotype.…”

Amygdala Kisspeptin Neurons: Putative Mediators of Olfactory Control of the Gonadotropic Axis

“…Currently, it is believed that Kiss1r is a G q/11 -coupled receptor, and therefore we would have expected that any direct effects of kisspeptin on mitral cells would be excitatory. However, we cannot exclude the possibility that kisspeptin couples to G proteins in a cell-specific manner [62] , and if Kiss1r on mitral cells is G i coupled, it may explain the observed inhibitory effect on electrical activity.…”

Uterine and placental KISS1 regulate pregnancy: what we know and the challenges that lie ahead

“…Centrally derived KISS1 (the 145 amino acid primary translation product of the KISS1 gene) and its derivatives (kisspeptins) are now well recognized as potent triggers of hypothalamic gonadotropin-releasing hormone (GnRH) secretion and thereby serve as pivotal regulators of the neuroendocrine-reproductive axis (reviewed in Millar & Babwah (2015)). Diminished hypothalamic kisspeptin signaling in man and mouse, as a consequence of inactivating mutations in the genes that encode either KISS1 or its cognate receptor, KISS1R, results in infertility.…”