A novel mammalian receptor for the evolutionarily conserved type II GnRH

Mammalian gonadotropin-releasing hormone (GnRH I: pGlu-His-TrpSer-Tyr-Gly-L eu-Arg-Pro-Gly-NH2) stimulates pituitary gonadotropin secretion, which in t urn stimulates the gonads. Whereas a hypothalamic form of GnRH of variable structure (designated type I) had been shown to regulate reproduction throu gh a cognate type I receptor, it has recently become evident that most vert ebrates have one or two other forms of GnRH. One of these, designated type II GnRH (GnRH II: pGlu-His-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2), is conserved f rom fish to man and is widely distributed in the brain, suggesting importan t neuromodulatory functions such as regulating K+ channels and stimulating sexual arousal. We now report the cloning of a type II GnRH receptor from m armoset cDNA. The receptor has only 41 % identity with the type I receptor and, unlike the type I receptor, has a carboxyl-terminal tail. The receptor is highly selective for GnRH II. As with the type I receptor, it couples t o G(alphaq/11) and also activates extracellular signal-regulated kinase (ER K1/2) but differs in activating p38 mitogen activated protein (MAP) kinase. The type II receptor is more widely distributed than the type I receptor a nd is expressed throughout the brain, including areas associated with sexua l arousal, and in diverse non-neural and reproductive tissues, suggesting a variety of functions. Surprisingly, the type II receptor is expressed in t he majority of gonadotropes. The presence of two GnRH receptors in gonadotr opes, together with the differences in their signaling, suggests different roles in gonadotrope functioning.