Endocrine Abstracts

GPR54 is a G protein coupled receptor identified in 2001 as the target for kisspeptin, the product of the KiSS-1 gene. Mutations in both kisspeptin and GPR54 lead to inherited failure to enter puberty (idiopathic hypogonadotropic hypogonadism) in the human, and a mutant mouse line with a targeted disruption of the Gpr54 receptor (Gpr54 -/-) has shown the same phenotype.

Puberty begins when neurons in the hypothalamus begin pulsatile secretion of GnRH. These neurons originate in the nasal compartment including the olfactory placode and the vomeronasal organ. GnRH neurons are inaccessible for study, given their dispersed nature in the hypothalamus. We wished to establish whether kisspeptin exerted a direct effect on human GnRH neurons and used a primary human olfactory epithelium GnRH expressing neuroblast (FNC-B4) primary culture to investigate this. By means of Fura-2 fluorescence imaging (Fucal, TILL Photonics, Germany), in preliminary experiments using appropriate positive (GnRH superactive analogue) and negative controls (vehicle, scrambled decapeptide), we have shown that FNC-B4 cells (n=60) generate intracellular calcium transients following 30 seconds of exposure to 10 and 100 micromolar of the N terminal decapeptide of kisspeptin, of greater amplitude to those of background transients. Kisspeptin may thus constitute an important direct input into GnRH secreting cells to initiate GnRH secretion and thereby initiate puberty. The pharmacological manipulation of this system offers the prospect of extending current knowledge of the neuroendocrine control of GnRH secretion: moreover, pharmacological manipulation of this system may hold promise in modulating reproductive competency in man.