The wonderful and masterful G protein-coupled receptor (GPCR): A focus on signaling mechanisms and the neuroendocrine control of fertility.

Human GnRH deficiency, both clinically and genetically, is a heterogeneous disorder comprising of congenital GnRH deficiency with anosmia (Kallmann syndrome), or with normal olfaction [normosmic idiopathic hypogonadotropic hypogonadism (IHH)], and adult-onset hypogonadotropic hypogonadism. Our understanding of the neural mechanisms underlying GnRH secretion and GnRH signaling continues to increase at a rapid rate and strikingly, the heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) continue to emerge as essential players in these processes. GPCRs were once viewed as binary on-off switches, where in the "on" state they are bound to their Gα protein, but now we understand that view is overly simplistic and does not adequately characterize GPCRs. Instead, GPCRs have emerged as masterful signaling molecules exploiting different physical conformational states of itself to elicit an array of downstream signaling events via their G proteins and the β-arrestins. The "one receptor-multiple signaling conformations" model is likely an evolved strategy that can be used to our advantage as researchers have shown that targeting specific receptor conformations via biased ligands is proving to be a powerful tool in the effective treatment of human diseases. Can biased ligands be used to selectively modulate signaling by GPCR regulators of the neuroendocrine axis in the treatment of IHH? As discussed in this review, the grand possibility exists. However, while we are still very far from developing these treatments, this exciting likelihood can happen through a much greater mechanistic understanding of how GPCRs signal within the cell.