Decoding high Gonadotropin-releasing hormone pulsatility: a role for GnRH receptor coupling to the cAMP pathway?

Abstract

The gonadotropin-releasing hormone (GnRH) pulsatile pattern is critical for appropriate regulation of gonadotrope activity but only little is known about the signaling mechanisms by which gonadotrope cells decode such pulsatile pattern. Here, we review recent lines of evidence showing that the GnRH receptor (GnRH-R) activates the cyclic AMP (cAMP) pathway in gonadotrope cells, thus ending a long-lasting controversy. Interestingly, coupling of GnRH-R to the cAMP pathway as well as induction of nitric oxide synthase 1 (NOS1) or follistatin through this signaling pathway take place preferentially under high GnRH pulsatility. The preovulatory surge of GnRH in vivo is indeed associated with an important increase of pituitary cAMP and NOS1 expression levels, both being markedly inhibited by treatment with a GnRH antagonist. Altogether, this suggests that due to its atypical structure and desensitization properties, the GnRH-R may continue to signal through the cAMP pathway under conditions inducing desensitization for most other receptors. Such a mechanism may contribute to decode high GnRH pulsatile pattern and enable gonadotrope cell plasticity during the estrus cycle.

Keywords: GnRH pulsatile pattern; GnRH receptor; cAMP pathway; gonadotrope cell signaling; pituitary.

FIGURE 1

Profiles of serum LH and pituitary cAMP and NOS1 levels during the proestrus and following administration of a GnRH antagonist. (A) Serum LH, pituitary cAMP, and pituitary NOS1 levels were determined by radioimmunoassay, ELISA, and western blot analysis, respectively. (B) Effect of an in vivo treatment with the GnRH antagonist, antarelix. ^aP <0.05 and ^bP <0.01 compared with proestrus, **P <0.01 compared with diestrus II. Modified from Kimura et al. (1980), Lozach et al. (1998), and Garrel et al. (2010).