Difference in receptor-binding contributes to difference in biological activity between the unique guinea pig GnRH and mammalian GnRH

Abstract

In the current study, we compared the in vitro potency of a unique form of gonadotropin-releasing hormone (GnRH) present in the brain of the guinea pig (gpGnRH) with that of mammalian GnRH (mGnRH) as well as their binding affinities to the GnRH receptor. In gpGnRH, the highly conserved histidine in position 2 (His(2)) and leucine in position 7 (Leu(7)) are substituted by tyrosine and valine, respectively. In vivo, gpGnRH was shown to be less potent than mGnRH, possibly in part because of higher susceptibility to enzymatic degradation. In the present in vitro experiments, we observed that gpGnRH was less potent than mGnRH in stimulating the release of luteinizing hormone (LH) from primary pituitary cell cultures of the rat, and at lower concentrations from primary pituitary cell culture of the guinea pig, too. These results were confirmed by radioligand-binding studies. It is concluded that the lower biological activity of gpGnRH in both rat and guinea pig may be explained by the difference in binding to the target cells, although additional factors such as proteolytic degradation may also contribute to the observed phenomenon.