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Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system Mead EJ; Maguire JJ; Kuc RE; Davenport APBr J Pharmacol 2007[Aug]; 151 (8): 1143-53Orphan G-protein-coupled receptors that have recently been paired with their cognate ligand are an often untapped resource for novel drug development. The KISS1 receptor (previously designated GPR54) has been paired with biologically active cleavage peptides of the KiSS-1 gene product, the kisspeptins (KP). The focus of this review is the emerging pharmacology and physiology of the KP. Genetic linkage analysis in humans revealed that mutations in KISS1 (GPR54, AXOR12 or hOT7T175) result in idiopathic hypogonadotrophic hypogonadism and knockout mouse studies confirmed this finding. Identification of KISS1 (GPR54) as a molecular switch for puberty subsequently led to the discovery that KP activate the GnRH cascade. Prior to the role of KISS1 (GPR54) in puberty being described, KP had been shown to be inhibitors of tumour metastasis across a range of cancers. Subsequently the mechanism of this inhibition has been suggested to be via altered cell motility and adhesiveness. PCR detected highest expression of KP and KISS1 (GPR54) in placenta, and changes in KP levels throughout pregnancy and expression in trophoblasts suggests a role in placentation. Placentation and metastasis are invasive processes that require angiogenesis. Investigation of KISS1 (GPR54) and KP in vasculature revealed discrete localisation of KISS1 (GPR54) to blood vessels prone to atherosclerosis and a potent vasoconstrictor action. A role for KP has also been shown in whole body homeostasis. KP are multifunctional peptides and further investigation is required to fully elucidate the complex pathways regulated by these peptides and how these pathways integrate in the whole body system.|Cardiovascular System/physiopathology[MESH]|Drug Delivery Systems[MESH]|Humans[MESH]|Kisspeptins[MESH]|Neoplasm Metastasis/physiopathology[MESH]|Neoplasms/physiopathology[MESH]|Receptors, G-Protein-Coupled/genetics/*physiology[MESH]|Receptors, Kisspeptin-1[MESH]|Reproduction/physiology[MESH]|Tumor Suppressor Proteins/genetics/pharmacology/*physiology[MESH] |
