Molecular biology of the kisspeptin receptor: signaling, function, and mutations.

Kisspeptin receptor (KISS1R) signaling is essential for the hallmark increase in pulsatile GnRH secretion characteristic of the onset of puberty in humans and experimental animals. Loss-of-function mutations in KISS1R are associated with idiopathic hypogonadotropic hypogonadism in humans. Also, mutations with confirmed association with idiopathic central precocious puberty were identified in kisspeptin and KISS1R. These observations underscore the role of KISS1R signaling for normal pubertal development. Moreover, investigation of the mechanisms underlying the gain-of-function mutation in KISS1R indicates that the duration of KISS1R signaling is critical for the role of this receptor in timing the onset of puberty in humans. These findings further endorse the need to uncover the mechanisms, as well as yet-unknown proteins, involved in each step of KISS1R signaling. This knowledge is expected to advance our understanding of normal and abnormal pubertal development, as well as to help uncover the role of KISS1R signaling in non-hypothalamic tissues such as the placenta. This chapter discusses recent advances in the investigation of KISS1R signaling and function, as well as potential pathophysiological implications of naturally occurring mutations in this receptor identified in humans with reproductive disorders.