Gonadotropin-Releasing Hormone Receptor Signaling: Biased and Unbiased

Gonadotropin-releasing hormone is a neuropeptide that acts via Gq coupled G-protein coupled receptors in the pituitary that mediate central control of reproduction. GnRH receptors (GnRHR) and GnRH ligands are also found in extra-pituitary sites including the CNS as well as reproductive tissues and cancer cells derived from such tissues. Much of the interest in the extra-pituitary receptors stems from the fact that they mediate anti-proliferative and/or pro-apoptotic effects and may therefore be directly targeted for cancer therapy. Type I mammalian GnRHR are atypical in that they do not bind to (or signal via) arrestins. In spite of this restriction on their signaling repertoire, there is good evidence for existence of multiple active GnRHR conformations and for activation of multiple upstream effectors (heterotrimeric and monomeric G-proteins). In this review GnRHR signaling is described, with emphasis on the relevance of functional selectivity for pharmacological characterization of GnRHR ligands, as well as its possible contribution to contextdependent GnRHR signaling and relevance for GnRHR-mediated effects on cell fate as well as GnRHR trafficking.