The GPR54-Kisspeptin complex in reproductive biology: neuroendocrine significance and implications for ovulation induction and contraception.
KISS1 encodes the kisspeptin (KP) family of peptides which were originally characterised as potent antimetastatic agents in breast cancer and malignant melanoma cells. One member of this family of arginine-phenylalanine amide peptides, KP-54, was subsequently identified as the natural ligand for the G-protein coupled receptor-54 (GPR54). In addition to its importance as a metastatic suppressor, KP has been found to play a major neuroregulatory role in governing endogenous gonadotropin release by its modulation of the hypothalamic-pituitary-gonadal (HPG) axis. In humans, KISS1 mRNA has been localised to the hypothalamic anteroventral periventricular nucleus and arcuate nucleus. Although GPR54 is expressed in human pituitary cells, it is not presently known if gonadotrope cells themselves are targets for significant KP activity. It was recently shown that full disruption of the KP/GPR54 complex resulted in hypogonadotropic hypogonadism. Indeed, evidence now suggests that KP/GPR54 signalling during gestation is necessary for sexual differentiation and implicates activation of the KP/GPR54 complex as the single most important upstream event regulating GnRH release. Several compelling studies have placed KP as the leading candidate molecule responsible for initiating puberty, making this receptor-ligand complex of fundamental importance to the neuroendocrinology of reproduction. Here, we discuss key KP/GPR54 discovery events and present an evolution of KP biology in the context of recent animal and human experimental work. With evidence pointing to proper KP/GPR54 signalling as the principal trigger for activation of GnRH neurons and subsequent ovulation, elucidation of how this pathway is modulated is likely to bring novel pharmacologic strategies for fertility treatment (and contraception) within reach. Because the physiological significance KP is now acknowledged to extend well beyond cancer biology (and may also contribute to the pathophysiology of pre-eclampsia), KP represents an exciting research theme in human reproductive biology and neuroendocrinology.
Sills
Eric Scott
ES
The Sims Institute/Sims International Fertility Clinic, Dublin, Ireland. drscottsills@sims.ie
Walsh
Anthony P H
AP
D000818:Animals; D003267:Contraception; D006801:Humans; D059648:Kisspeptins; D010062:Ovulation Induction; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D000074502:Receptors, Kisspeptin-1; D012098:Reproduction / Q000502:physiology; D012741:Sexual Maturation / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
C106628:KISS1 protein, human; C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D025521:Tumor Suppressor Proteins