KiSS1-derived peptide receptor

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]

KISS1R
Identifiers
Aliases	KISS1R, AXOR12, CPPB1, GPR54, HH8, HOT7T175, KISS-1R, KiSS1-derived peptide receptor, KISS1 receptor
External IDs	OMIM: 604161; MGI: 2148793; HomoloGene: 11411; GeneCards: KISS1R; OMA:KISS1R - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.3 Start 917,287 bp[1] End 921,005 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10|10 C1 Start 79,752,805 bp[2] End 79,758,107 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Pons endothelial cell Hypothalamus Brodmann area 23 pancreatic ductal cell cartilage tissue superior vestibular nucleus nucleus accumbens blood cingulate gyrus Top expressed in granulocyte substantia nigra embryo embryo primary visual cortex neuron dentate gyrus of hippocampal formation granule cell superior frontal gyrus right kidney cerebellar cortex More reference expression data BioGPS n/a
Gene ontology Molecular function G protein-coupled peptide receptor activity G protein-coupled receptor activity neuropeptide receptor activity signal transducer activity protein binding Cellular component integral component of membrane intracellular membrane-bounded organelle membrane plasma membrane integral component of plasma membrane cell surface cilium Biological process phospholipase C-activating G protein-coupled receptor signaling pathway signal transduction neuropeptide signaling pathway G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 84634 114229 Ensembl ENSG00000116014 ENSMUSG00000035773 UniProt Q969F8 Q91V45 RefSeq (mRNA) NM_032551 NM_053244 NM_001359010 RefSeq (protein) NP_115940 NP_444474 NP_001345939 Location (UCSC) Chr 19: 0.92 – 0.92 Mb Chr 10: 79.75 – 79.76 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

PDB: 8ZJD. Proteins shown: Kisspeptin-10 (Dark Orange), KISS1R (Teal), Gαi/Gαq Subunit (Yellow), Gβ Subunit (Purple), Gγ Subunit (Purple), scFv16 (Pink).

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

• 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