Mammalian protein found in Homo sapiens
The KiSS1-derived peptide receptor (also known as GPR54 or the Kisspeptin receptor) is a G protein-coupled receptor[5] which binds the peptide hormone kisspeptin (metastin).[6][7][8] Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues.[9] Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.[10]
Kisspeptins are neuropeptides synthesized in the hypothalamus and encoded by the KISS1 gene. The KISS1 gene encodes the G protein-coupled receptor 54 (known as KISS1R or GPR54) and plays a crucial role in regulating reproduction, pubertal maturation, and metabolic function.[11][12][13] KISS1 neurons located in the arcuate nucleus (ARC) of the mediobasal hypothalamus (MBH) project to GnRH neurons in the median eminence, which expresses KISS1R, to stimulate LH secretions in a pulsatile manner from the anterior pituitary to initiate ovulation/ pubertal maturation.[14][15][16] The KISS1 and KISS1R/GPR54 genes have been detected in the brain, pituitary, placenta, pancreas, liver, and small intestine.[14]
Function
Kisspeptin is involved in the regulation of endocrine function and the onset of puberty, with activation of the kisspeptin receptor triggering release of gonadotropin-releasing hormone (GnRH),[17][18] and release of kisspeptin itself being inhibited by oestradiol but enhanced by GnRH.[19] Reductions in kisspeptin levels with age may conversely be one of the reasons behind age-related declines in levels of other endocrine hormones such as luteinizing hormone.[20]
Clinical significance
Alterations in the KISS1/KISS1R signaling pathway have been linked to multiple physiological conditions, including metabolic and reproductive abnormalities.[21] A knockout model of GPR54/KISS1R in mice showed hypogonadism, and the mice failed to reach puberty.[21] The KISS1 gene has been stated to suppress the metastasis of malignant melanomas.[22] KISS1R signaling pathway has been characterized in the suppression of tumors and has anti-metastatic effects in several cancers, including breast cancer.[23][24]
Activation of KISS1R elicits a neuroendocrine response leading to pubertal maturation. This is indicated by intermittent kisspeptin-10 administration to pre-pubertal animals resulting in activation of the hypothalamic-pituitary axis and subsequent precocious puberty in rats and primates.[25][26] Mutations in the kisspeptin receptor KISS1R have resulted in isolated hypogonadotropic hypogonadism (IHH), characterized by delayed or absence of puberty [27]
Ligands
No non-peptide ligands for this receptor have yet been discovered, but as of 2009 both selective agonist and antagonist peptides are known.
Agonists
- Kisspeptin (kisspeptin-54, metastin)
- Kisspeptin-10 (112-121 C-terminal fragment)[28]
- KISS1-305
- MVT-602 (RVT-602, TAK-448)
- TAK-683
Antagonists
- Kisspeptin-10 analogues modified with amino substitutions[29]
- Kisspeptin-234