The Biological function of Kisspeptin 10

Introduction

Kisspeptin (KISS1) is an amidated neurohormone first identified as a key regulator involved in GnRH control at the level of the hypothalamus. KISS1 gene encodes a 145-amino acids precursor protein that can originate four possible derivate peptides with 54-, 14-, 13- or 10-amino acids. All these peptides have the same efficacy and affinity for their receptor, GPR54, being kisspeptin-10 the most commonly used in biomedical research. In addition to its central effects, KISS1 and its receptor (GPR54, KISS1R or AXOR12) are widely distributed in different tissues, including the pituitary gland, suggesting that this neurohormone system could play an important role in the control of hypophyseal hormone release. Specifically, in non-human primates (Macaca mulatta), kisspeptin-positive cells have been described to be present in the intermediate lobe co-localizing with α-MSH, in the neural lobe with GnRH axons, and only in 50% with ACTH-positive cells in the periphery of the anterior lobe of the pituitary[1].

Human studies of kisspeptin have hitherto used the 54-amino acid peptide kisspeptin-54. Kisspeptin-54 is cleaved from the 145-amino acid precursor polypeptide encoded by KISS1 and is further processed to 14, 13, and 10 amino acids (kisspeptin-10) sequences, all sharing the same C-terminal decapeptide RFAmide (arginine-amidated phenylalanine) sequence. Kisspeptin-10 is a synthetic peptide sequence: Tyr–Asn–Trp–Asn–Ser–Phe–Gly–Leu–Arg–Phe–NH2. Although kisspeptin-10 has intrinsic bioactivity similar to the longer kisspeptin fragments, it is also characterized by a shorter half-life and more rapid onset of action after iv administration in rodents. Kisspeptin-10 also has greater potential for pharmaceutical development because agonists and antagonists have been developed based on its decapeptide sequence[2].

Biological function

In humans, kisspeptin-54 and kisspeptin-10 were able to similarly induce LH and FSH levels. However, both kisspeptins were less potent in stimulating gonadotropins levels than GnRH. Furthermore, intravenous administration of kisspeptin-10 in Macaca mulatta increased LH levels, an effect mediated by hypothalamic actions (GnRH-induced), while other hypophyseal hormones were not altered. In addition, results from studies on women did not confirm the role of kisspeptin on GH, TSH and PRL release after acute or chronic administration. However, kisspeptins seem to directly affect primary pituitary cell cultures from baboons. Specifically, kisspeptin-10 stimulated GH and LH secretion and mRNA levels after short- and long-term exposure (4–48 h) at a broad range of doses (10−14 to 10−6)[3].

In contrast, Kisspeptin 10 (human) did not alter FSH, PRL, ACTH or TSH secretion/expression. The signalling pathways involved in regulating GH and LH pituitary hormones by kisspeptins were phospholipase C, protein kinase C, MAPK, and intracellular Ca2+ mobilization. Interestingly, the release of LH, but not GH, involved the mammalian targets of rapamycin (mTOR) and PI3K. Taken together, in vitro and in vivo evidence suggest that kisspeptins could play a relevant role, at least, in LH regulation and seem to exert the effects not only through hypothalamic actions but also directly on the pituitary gland.

An irrefutable gatekeeper of pubertal function, kisspeptin-10 (KP-10), which is proteolytically liberated from a 145 amino acid precursor protein and biologically governed by its G-protein-coupled receptor, GPR54, inhibited the noxious insults of extracellular amyloid β-proteins (Aβ) via an action that GPR54 antagonists could not impede. Concomitantly, genetic ablation of the KISS1 gene, which encodes kisspeptin, exacerbated Aβ-induced toxicity, while KISS1-overexpressing neurons established a cellular milieu impervious to Aβ toxicity[4]. The laboratory demonstrated that exogenously administered KP-10 was efficacious in attenuating the progressive demise of α-syn-rich cholinergic neurons in vitro. Under explicitly modelled environments, KP-10 unambiguously accommodated in the C-terminal binding pockets of α-syn despite solvent-driven perturbations, thus reflecting the existence of a putative binding site. The functional relevance of KP-10 binding mechanisms can be insinuated in the amelioration of α-syn-mediated neurotoxicity.

References

[1] J T George. “Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men.” Journal of Clinical Endocrinology & Metabolism 96 8 (2011): E1228-36.

[2] Paulina Radwańska. “Kisspeptin-10 increases collagen content in the myocardium by focal adhesion kinase activity.” Scientific Reports 13 1 (2023): 19977.

[3] M.C. Vázquez-Borrego . “Multiple signaling pathways convey central and peripheral signals to regulate pituitary function: Lessons from human and non-human primate models.” Molecular and Cellular Endocrinology 463 (2018): Pages 4-22.

[4] Christopher Simon, Ishwar Parhar, Tomoko Soga. “Kisspeptin-10 Mitigates α-Synuclein-Mediated Mitochondrial Apoptosis in SH-SY5Y-Derived Neurons via a Kisspeptin Receptor-Independent Manner.” International Journal of Molecular Sciences 24 7 (2023).

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