Kisspeptin isoforms: versatile players in reproduction and beyond

Kisspeptin and its cognate G-protein-coupled receptor (GPCR), the kisspeptin-1 receptor (KISS-1R), are central to mammalian reproduction, regulating the hypothalamic-pituitary-gonadal axis. They are upstream regulators of gonadotropin-releasing hormone (GnRH) secretion, a hallmark of the onset of puberty, subsequently tuning luteinizing hormone and follicle-stimulating hormone levels and bringing about steroid hormone production. In mammals, kisspeptin (Kp) is synthesized as a 145-mer pre-pro-polypeptide by the KISS1 gene, which further undergoes cleavage to form four kisspeptin isoforms: Kp-54, Kp-14, Kp-13 and Kp-10. They all share a common decapeptide sequence (Kp-10), followed by an RF-amide in their C-terminal end. Kp-10, the smallest isoform, is reported to activate KISS-1R to its full functional potential. The reproductive roles of Kp-54 and Kp-10 have been studied extensively by in vivo and clinical studies owing to their longer terminal half-life and commercial bargain, respectively. This comprehensive review aims to collate the multitude of functions displayed by all naturally occurring kisspeptin isoforms and other kisspeptin-like peptides in reproduction and beyond, including metabolic regulation and therapeutic potential. The structural architecture of kisspeptin isoforms reported using alanine scan substitution studies and secondary structure using circular dichroism and nuclear magnetic resonance spectroscopy studies have also been highlighted. Several kisspeptin agonists and antagonists have been developed for ovulation induction in assisted reproduction and management of pubertal disorders. This review summarizes the diverse roles and structural insights of kisspeptin isoforms to help in the identification of new horizons and thematic areas for basic and translational research, culminating in potential therapeutic applications.