Kisspeptin 1 receptor (KISS1R)

The Kisspeptin 1 receptor (KISS1R), also known as GPR54, is a G protein-coupled receptor primarily expressed on gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus. It serves as a critical neuroendocrine gatekeeper for the onset of puberty and the regulation of the hypothalamic-pituitary-gonadal (HPG) axis by mediating the effects of its endogenous ligands, the kisspeptins. Activation of KISS1R triggers the release of GnRH, which in turn stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. Beyond its central role in reproduction, KISS1R was originally identified as a metastasis suppressor (metastin receptor), where its activation inhibits the migration and invasion of various cancer cells, including melanoma and breast cancer. Therapeutically, KISS1R is a significant target for treating reproductive disorders such as hypogonadotropic hypogonadism and infertility through the use of potent agonists like MVT-602. Conversely, KISS1R antagonists are being explored for the management of sex steroid-dependent conditions, including precocious puberty and certain hormone-sensitive cancers. The receptor also integrates metabolic signals from hormones like leptin and insulin, making it a vital link between energy homeostasis and reproductive capacity. Its diverse roles in both endocrine signaling and oncology make it a versatile target for drug development in reproductive medicine and cancer therapeutics.

Other names

GPR54AXOR12hOT7T175Metastin receptorKiSS-1 receptorCPPB1HH8

Agonism of KISS1R activates the Gq/11 signaling pathway, leading to phospholipase C activation, inositol trisphosphate (IP3) production, and intracellular calcium mobilization, which stimulates the pulsatile release of GnRH. Antagonism blocks this pathway to suppress the hypothalamic-pituitary-gonadal axis.