Mechanistic insights into the more potent effect of KP-54 compared to KP-10 in vivo.

Abstract

Kisspeptins are a family of neuropeptides encoded by the Kiss1 gene that are critical for activation of the mammalian reproductive axis at puberty [1] and regulation of ovulation in sexually mature females [2]. In humans , they are generated from a 145- amino acid precursor to produce smaller amidated peptides of 54, 14, 13 or 10- amino acids that all share the common C-terminal decapeptide sequence. Kisspeptins act via the G-protein coupled receptor, KISS1R (also known as GPR54) to stimulate GnRH release and subsequent secretion of gonadotrophic hormones (LH and FSH) in all mammalian species examined [3–8]. Inactivating mutations in KISS1R or KISS1 cause hypogonadotrophic hypogonadism in humans and mice [1, 9–11].The potency of the different kisspeptins has been examined both in vitro and in vivo. In general, all forms of kisspeptin show similar receptor binding affinities and cell signalling properties in vitro [12]. KP-10 exerts a potent direct depolarizing action on GnRH neurons and increases their firing rate in acute brain slices [13]. Moreover, KP-54 and KP-10 induce robust LH release after direct delivery into the brain with similar effects [3]. In contrast, KP-54 and KP-10 have different potencies when they are delivered systemically. This is particularly relevant for the proposed clinical use of kisspeptins , as they will most likely be administered peripherally rather than directly into the brain . Peripheral delivery of KP-54 stimulated release of LH over a sustained period of 1 to 4 hours, while KP-10 induced less sustained LH secretion between 10 min to 1 h [5, 14–18]. The reason for this difference in the potency of KP-54 and KP-10 after systemic delivery is not known. It may be caused by differences in the half-life of each peptide in the blood stream or by differences in their ability to cross the blood-brain barrier . We have directly compared KP-54 and KP-10 to gain an insight into why KP-54 elicits more sustained responses than KP-10 after systemic delivery. This knowledge will be relevant when considering which form of kisspeptin to use in a clinical setting and in understanding the mechanisms of action of the different kisspeptins .