Results Probl Cell Differ DOI 10.1007/400_2007_050/Published online: 12 January 2008  Springer-Verlag Berlin Heidelberg 2008 GPR54 and Kisspeptins W. H. Colledge Physiological Laboratory, Dept. of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK Whc23@cam.ac.uk Abstract The G-protein coupled receptor GPR54 has an essential role in the initiation and maintenance of mammalian fertility. Humans and mice with mutations in GPR54 have hypogonadotropic hypogonadism characterized by absence of sexual maturation and low levels of gonadotropic hormones (LH and FSH). The ligand for GPR54 is encoded by the KISS1 gene, which produces a 54-amino-acid peptide (metastin or kisspeptin-54) that can be cleaved into shorter peptides (kisspeptins 14, 13 and 10) with similar potencies. Kisspeptin administration stimulates gonadotropin release in several species by induc- ing GnRH secretion from hypothalamic GnRH neurons expressing GPR54. Kisspeptins are produced by neurons located in the AVPV and ARC regions of the hypothalamus. Expression of Kiss1 in these neurons is differentially regulated by sex steroids providing a mechanism by which testosterone or estrogen can regulate GnRH release. The AVPV region is sexually dimorphic with highest expression of kisspeptin in females. Positive feedback by estrogen on expression of Kiss1 in the AVPV region may be responsible for the pre-ovulatory LH surge during the estrus cycle. Central administration of kisspeptin to immature female rats can induce precocious activation of the gonadotropic axis, caus- ing advanced vaginal opening, elevated uterus weight, increased serum levels of LH and estrogen and induce ovulation. Kisspeptins/GPR54 have also been implicated in regulat- ing the estrus cycle of seasonal breeders and in the control of lactational amenorrhea. Expression of Gpr54 and Kiss1 have also been reported in several peripheral tissues in- cluding the pituitary, ovary, testes and the placenta raising the possibility that these genes may have additional functions in these tissues. Regulation of kisspeptin expression by peripheral factors such as leptin may be involved in coordinating metabolic status with the reproductive axis. 1 Introduction Mammalian reproductive function is regulated by hormonal messengers and feedback loops within the hypothalamic-pituitary-gonadal axis (Fig. 1A). At puberty, neurons in the medial preoptic area of the hypothalamus initi- ate the pulsatile secretion of gonadotropin releasing hormone (GnRH) into the portal blood system for delivery to the anterior pituitary. Within the pituitary, GnRH stimulates gonadotropic cells to release the gonadotropic hormones luteinizing hormone (LH) and follicle stimulating hormone (FSH). The gonadotropins act on the gonads to stimulate synthesis of the sex steroids (testosterone and estrogen) which are required for spermato-