Newly recognized GnRH receptors: function and relative role

Hypothalamic gonadotropin releasing hormone (GnRH 1) and its pituitary receptor are responsible for the CNS regulation of reproduction. However, a second GnRH (GnRH II) is also expressed in humans and a gene that resembles the GnRH II receptor in fish has been identified in humans and monkeys. The amino-acid sequence of this newly identified, seven-transmembrane, G-protein-coupled receptor in monkeys differs from the human GnRH I receptor by having a C-terminal, cytoplasmic tail. GnRH II is similar to400-fold more potent at GnRH II receptors than GnRH I receptors. GnRH I directly inhibits proliferation of human tumor cells, and GnRH II and its receptor might have a similar role. Limited progress has been made, however, because of difficulty translating the mRNA that encodes the human GnRH II receptor. Nevertheless, such receptors are likely to exist in humans because GnRH II is more inhibitory to tumor cell replication than GnRH I, and GnRH I and GnRH II have reciprocal effects on human decidual stromal cells in culture. The focus of this review is the identity of a possible translatable, functional GnRH II receptor in humans. The two possibilities considered are either that GnRH II receptor mRNA is expressed that encodes either 5 or 7 transmembrane domains or that a GnRH II-responsive complex is formed by the GnRH I receptor and fragments derived from the GnRH II receptor.