Kisspeptin and the KISS1R/GPR54 Receptor: What Animal and Cell Signalling Studies Report

Kisspeptin, the peptide product of the KISS1/Kiss1 gene, binds the G protein-coupled receptor KISS1R (also designated GPR54), which is expressed by gonadotropin-releasing hormone (GnRH) neurons in mammals [1]. Reviews of rodent work describe kisspeptin neurons making close contact with GnRH neurons at both the cell body and nerve terminals, with receptor activation reported to stimulate GnRH release and activation of the reproductive axis in mammalian models [1]. Genetic studies summarised in the literature report that mutations in the receptor in humans, and targeted deletions of Kiss1 or Kiss1r in mice, are associated with hypogonadotropic hypogonadism and absent puberty [3][4]; the mouse data were interpreted as confirming the ligand-receptor pair's role in the control of puberty and reproductive function in that species [4]. At the level of single-cell electrophysiology in native GnRH neurons, reviews of rodent recordings describe both presynaptic and postsynaptic actions, with the postsynaptic component reported to dominate excitability [2]. Presynaptically, kisspeptin was reported to increase GABA-A and glutamate drive onto GnRH neurons; postsynaptically, it was reported to inhibit an A-type current and inwardly rectifying potassium currents (Kir 6.2 and GIRK) and to activate non-selective cation (TRPC) currents, producing long-lasting depolarisation and increased action potential firing [2]. A parallel review of GnRH neuronal signalling describes the same pattern of potassium channel inhibition and cation channel activation, acting either directly on GnRH neurons or indirectly via synaptic input from other neurons, and notes that these circuits are integrated differently across species [1]. Anatomical and regulatory descriptions from multi-species work report that Kiss1-expressing neurons occupy discrete hypothalamic nuclei as well as other brain regions in many vertebrates, with distribution, regulation and function varying widely between species [3]. These neurons were reported to express estrogen and androgen receptors, making them direct targets of gonadal steroid action in male and female animals, and to show sexual differentiation in cell number and transcriptional activity in certain nuclei; some were reported to co-express dynorphin and neurokinin B [3]. Reviews of female mammalian physiology describe two principal populations, in the rostral periventricular area of the third ventricle and in the arcuate/infundibular nucleus, with the arcuate/infundibular population discussed as a GnRH pulse generator under steroid negative feedback and the rostral population associated with the steroid-driven preovulatory surge [10]. Kisspeptin signalling in the brain has also been implicated in seasonal reproduction, the tempo of sexual maturation, and restraint of reproductive activity during lactation in animal models [3], and reviews of the ligand and receptor note multiple Kiss and Kissr gene forms across non-mammalian vertebrates compared with the single ligand and receptor retained in higher mammals [10]. Intracellular signalling reviews report that KISS1R couples to Gαq/11 and recruits both G protein- and β-arrestin-dependent pathways, with rapid desensitisation, internalisation and recycling of resensitised receptors discussed as mechanisms maintaining a surface receptor population during prolonged stimulation; desensitisation studies have been reported in humans and in domestic and laboratory animals [7]. Work in transfected cells reported that KISS1R forms heterocomplexes with the G protein-coupled estrogen receptor (GPER) and that complex formation reduced KISS1R-mediated signalling by limiting receptor cell-surface expression rather than by blocking ligand-induced conformational change [8]. Peptide and small-molecule kisspeptin antagonists have been described and used as tools to delineate kisspeptin's role within the reproductive system [9]. Beyond GnRH neurons, a mouse study reported Kiss1r expression in astrocytes in vivo and in astrocyte cultures from mice, rats and humans, where kisspeptin activated canonical intracellular signalling pathways [6]. Conditional ablation of Kiss1r in GFAP-positive cells in mice was reported to alter astrocyte gene expression related to PGE2 synthesis, perturb astrocyte-GnRH neuronal appositions, and change LH responses to kisspeptin and LH pulsatility, as well as reproductive responses to a high-fat diet including pubertal onset and estrous cyclicity [6]. Separately, reviews note that failure of GnRH-1 neurons to complete their developmental migration from the olfactory placode to the hypothalamus results in failure of the reproductive axis in mammals [20]. Peripheral models have also been examined. A rat model of polycystic ovary syndrome induced with testosterone propionate and a high-fat diet reported elevated kisspeptin and GPR54 expression together with reduced SHBG, and cell experiments in HepG2 cells reported that kisspeptin-54 increased AKT phosphorylation and lowered SHBG protein [12]. In vascular research, kisspeptin-10 and GPR54 were reported to be expressed in atheromatous plaques, with in vitro effects on human endothelial cells, monocyte adhesion, foam cell formation and aortic smooth muscle cells, and with infusion in Apoe-knockout mice reported to accelerate aortic lesion development; these effects were reported to be attenuated by the GPR54 antagonist P234 in the same mouse model [13]. Reviews of the urogenital system describe kisspeptin-KISS1R involvement in oocyte development, spermatogenesis and sperm capacitation, and report altered kisspeptin and/or KISS1R expression in chronically impaired kidneys in preclinical animal models [14]. In cancer biology, KISS1 has been described as a metastasis-suppressor gene in many human tumours, while reviews of triple-negative breast cancer report KISS1R signalling promoting invadopodia formation and cross-talk with EGFR, AXL and TGF-β in that context [15]. In human precision-cut liver slices and human hepatic stellate cell lines, a kisspeptin analogue was reported to lower collagen secretion and fibrogenic and inflammatory marker expression, with reduced SMAD2/3 phosphorylation attributed to PP2A activation [16]; the same report noted that kisspeptin had previously been reported to affect steatosis and fibrosis in mouse models via KISS1R [16]. Transcriptomic and functional work in endometriosis reported KISS1R among progressively altered genes in patient endometrium and, in cell and animal experiments, reduced endometrial cell invasion and angiogenesis associated with lower PI3K and AKT phosphorylation and increased CREB5 [17]. Human-focused reviews summarise that inactivating receptor mutations are associated with normosmic hypogonadotropic hypogonadism, that signalling-enhancing variants have been associated with gonadotropin-dependent precocious puberty, and that acute intravenous kisspeptin administration in healthy male volunteers raised plasma LH, FSH and testosterone [19]. Circulating kisspeptin was reported at low concentrations in men and non-pregnant women and markedly higher in pregnancy, with the placenta identified as the presumed source [19]. Further reviews discuss genetic variants affecting receptor signalling and summarise data on KISS1R agonists under investigation [18], and earlier reviews cover the physiology of the signalling system in relation to gonadotropin and gonadal steroid secretion and its relevance to idiopathic hypogonadotropic hypogonadism [5][11].