Kisspeptin/Kisspeptin Receptor System in the Ovary

Abstract

Kisspeptins are a family of neuropeptides that are critical for initiating puberty and regulating ovulation in sexually mature females via the central control of the hypothalamic-pituitary-gonadal axis. Recent studies have shown that kisspeptin and its receptor kisspeptin receptor (KISS1R) are expressed in the mammalian ovary. Convincing evidence indicates that kisspeptins can activate a wide variety of signals via its binding to KISS1R. Experimental data gathered recently suggest a putative role of kisspeptin signaling in the direct control of ovarian function, including follicular development, oocyte maturation, steroidogenesis, and ovulation. Dysregulation or naturally occurring mutations of the kisspeptin/KISS1R system may negatively affect the ovarian function, leading to reproductive pathology or female infertility. A comprehensive understanding of the expression, actions, and underlying molecular mechanisms of this system in the human ovary is essential for novel approaches to therapeutic and diagnostic interventions in reproductive diseases and infertility.

Keywords: follicular development; kisspeptin; kisspeptin receptor; kisspeptin signaling; oocyte maturation; ovarian function; ovulation; steroidogenesis.

Figure 1

Major structural features of human kisspeptins, the products of the Kiss1 gene. Different kisspeptins are generated by the cleavage from a common precursor, the prepro-kisspeptin. The prepro-kisspeptin contains 145 amino acids, with a 19-amino acid signal peptide and a central 54-amino acid region, kisspeptin-54 (Kp-54; formerly termed as metastin). Further cleavage of metastin generates kisspeptins of lower molecular weight: kisspeptin-14 (Kp-14), Kp-13, and Kp-10. All kisspeptins contain the RF-amide motif that is able to bind and activate kisspeptin receptor. Modified from Ref. (6).

Figure 2

Kisspeptin/kisspeptin receptor (KISS1R) signaling at a glance. KISS1R is a seven-transmembrane domain, Gq/11-coupled receptor. Upon binding of kisspeptin, the intracellular portion of KISS1R phosphorylates Gq/11. The α-subunit of Gq/11 activates PLC, which cleaves PIP2 into IP3 and DAG. IP3 promotes intracellular Ca²⁺ release from the endoplasmic reticulum, while DAG activates a signaling cascade by phosphorylating PKC. PKC activation induces the phosphorylation of MAP kinases, such as ERK1/2 and p38. In addition, activation of KISS1R recruits arrestin-1 and -2, which downregulated and upregulated phosphorylated ERK1/2 levels, respectively. The activation of KISS1R can stimulate or inhibit the phosphorylation of PI3K/Akt, depending on the cell types, but the intermediator is not investigated. Activated KISS1R also enhances the expression of MMP-9 via PI3K/Akt/NF-κB or ERK/NF-κB signaling. DAG, diacylglycerol; ERK1/2, extracellular signal-regulated kinase; IP3, inositol 1,4,5-triphosphate; PI3K, phosphatidylinositol-3-kinase; MMP-9, matrix metalloproteinase-9; NF-κB, nuclear factor κB; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C.

Figure 3

Potential mechanisms involved in the direct ovarian effects of the kisspeptin/kisspeptin receptor (KISS1R) system. Kisspeptin and KISS1R are expressed in ovarian cells. This locally produced kisspeptin might regulate follicular development, oocyte maturation, ovulation, and steroidogenesis in a paracrine or autocrine manner. Solid arrows stand for actions that have been clearly demonstrated in ovarian cells. Dotted arrows reflect potential pathways that could be involved in mediating the intraovarian kisspeptin/KISS1R effects, which have been proposed.