Inotropic action of the puberty hormone kisspeptin in rat, mouse and human: cardiovascular distribution and characteristics of the kisspeptin receptor.

Kisspeptins, the ligands of the kisspeptin receptor known for its roles in reproduction and cancer, are also vasoconstrictor peptides in atherosclerosis-prone human aorta and coronary artery. The aim of this study was to further investigate the cardiovascular localisation and function of the kisspeptins and their receptor in human compared to rat and mouse heart. Immunohistochemistry and radioligand binding techniques were employed to investigate kisspeptin receptor localisation, density and pharmacological characteristics in cardiac tissues from all three species. Radioimmunoassay was used to detect kisspeptin peptide levels in human normal heart and to identify any pathological changes in myocardium from patients transplanted for cardiomyopathy or ischaemic heart disease. The cardiac function of kisspeptin receptor was studied in isolated human, rat and mouse paced atria, with a role for the receptor confirmed using mice with targeted disruption of Kiss1r. The data demonstrated that kisspeptin receptor-like immunoreactivity localised to endothelial and smooth muscle cells of intramyocardial blood vessels and to myocytes in human and rodent tissue. [(125)I]KP-14 bound saturably, with subnanomolar affinity to human and rodent myocardium (K(D) = 0.12 nM, human; K(D) = 0.44 nM, rat). Positive inotropic effects of kisspeptin were observed in rat, human and mouse. No response was observed in mice with targeted disruption of Kiss1r. In human heart a decrease in cardiac kisspeptin level was detected in ischaemic heart disease. Kisspeptin and its receptor are expressed in the human, rat and mouse heart and kisspeptins possess potent positive inotropic activity. The cardiovascular actions of the kisspeptins may contribute to the role of these peptides in pregnancy but the consequences of receptor activation must be considered if kisspeptin receptor agonists are developed for use in the treatment of reproductive disorders or cancer.

International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin receptor nomenclature, distribution, and function.

Kisspeptins are members of the Arg-Phe amide family of peptides, which have been identified as endogenous ligands for a G-protein-coupled receptor encoded by a gene originally called GPR54 (also known as AXOR12 or hOT7T175). After this pairing, the gene has been renamed KISS1R. The International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification recommends that the official name for the receptor is the kisspeptin receptor to follow the convention of naming the receptor protein after the endogenous ligand. The endogenous ligand was initially called metastin, after its role as a metastasis suppressor, and is now referred to as kisspeptin-54 (KP-54), a C-terminally amidated 54-amino acid peptide cleaved from the 145-amino acid gene product. Shorter C-terminal cleavage fragments [KP-14, KP-13 and KP-10 (the smallest active fragment)] are also biologically active. Both receptor and peptide are widely expressed in human, rat, and mouse; the receptor sequence shares more than 80% homology in these species. Activation of the kisspeptin receptor by kisspeptin is via coupling to G(q/11) and the phospholipase C pathway, causing Ca(2+) mobilization. Mutations in the KISS1R gene result in hypogonadotropic hypogonadotropism, and targeted disruption of Kiss1r in mice reproduces this phenotype, which led to the discovery of the remarkable ability of the kisspeptin receptor to act as a molecular switch for puberty. In addition to regulating the reproductive axis, the kisspeptin receptor is also implicated in cancer, placentation, diabetes, and the cardiovascular system.