The KiNG of reproduction: Kisspeptin/ nNOS interactions shaping hypothalamic GnRH release

Gonadotropin-releasing hormone (GnRH) is the master regulator of the hypothalamic-pituitary-gonadal (HPG) axis, and therefore of fertility and reproduction. The release pattern of GnRH by the hypothalamus includes both pulses and surges. However, despite a considerable body of evidence in support of a determinant role for kisspeptin, the mechanisms regulating a GnRH pulse and surge remain a topic of debate. In this review we challenge the view of kisspeptin as an absolute “monarch”, and instead present the idea of a Kisspeptin-nNOS-GnRH or “KiNG” network that is responsible for generating the “GnRH pulse” and “GnRH surge”. In particular, the neuromodulator nitric oxide (NO) has opposite effects to kisspeptin on GnRH secretion in many respects, acting as the Yin to kisspeptin's Yang and creating a dynamic system in which kisspeptin provides the “ON” signal, promoting GnRH release, while NO mediates the “OFF” signal, acting as a tonic brake on GnRH secretion. This interplay between an activator and an inhibitor, which is in turn fine-tuned by the gonadal steroid environment, thus leads to the generation of GnRH pulses and surges and is crucial for the proper development and function of the reproductive axis. •nNOS neurons use local signaling when their activity is sparse or uncoordinated, and volume signaling when synchronous.•Kisspeptin can promote nNOS phosphorylation, enabling nNOS synchronous activity and subsequently NO release.•NO has opposite effects to kisspeptin on GnRH secretion.•NO acts as a brake allowing GnRH neurons to better synchronize, priming them for the excitatory kisspeptin stimulus.•NO and kisspeptin, by acting as the Yin and Yang of the GnRH axis may shape GnRH pulses and surges.