KiSS1-derived peptide receptor

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Template:Short description Template:Infobox gene

The KiSS1-derived peptide receptor (also known as GPR54 or the Kisspeptin receptor) is a G protein-coupled receptor[1] which binds the peptide hormone kisspeptin (metastin).[2][3][4] Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues.[5] Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.[6]

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.[7][8][9] 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.[10][11][12] The KISS1 and KISS1R/GPR54 genes have been detected in the brain, pituitary, placenta, pancreas, liver, and small intestine.[10]

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),[13][14] and release of kisspeptin itself being inhibited by oestradiol but enhanced by GnRH.[15] 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.[16]

Clinical significance

Alterations in the KISS1/KISS1R signaling pathway have been linked to multiple physiological conditions, including metabolic and reproductive abnormalities.[17] A knockout model of GPR54/KISS1R in mice showed hypogonadism, and the mice failed to reach puberty.[17] The KISS1 gene has been stated to suppress the metastasis of malignant melanomas.[18] KISS1R signaling pathway has been characterized in the suppression of tumors and has anti-metastatic effects in several cancers, including breast cancer.[19][20]

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.[21][22] Mutations in the kisspeptin receptor KISS1R have resulted in isolated hypogonadotropic hypogonadism (IHH), characterized by delayed or absence of puberty [23]

File:KISS1R Crystal Structure Orientation 2.png
PDB: 8ZJD. Proteins shown: Kisspeptin-10 (Dark Orange), KISS1R (Teal), Gαi/Gαq Subunit (Yellow), Gβ Subunit (Purple), Gγ Subunit (Purple), scFv16 (Pink).
File:KISS1R Crystal Structure Orientation 1.png
PDB: 8ZJD. Proteins shown: Kisspeptin-10 (Dark Orange), KISS1R (Teal), Gαi/Gαq Subunit (Yellow), Gβ Subunit (Purple), Gγ Subunit (Purple), scFv16 (Pink).

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

Antagonists

References

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Further reading

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External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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