Among the many endogenous peptides studied for their possible roles in hormone signaling systems associated with puberty and reproduction is Kisspeptin-10, also known as Metastin. This naturally occurring protein also seems to have other research applications.
Among its many functions, Kisspeptin-10 seems to affect mood and behavior, promote angiogenesis, and control renal function. Studies suggest it may also inhibit tumor development and prevent metastasis. From a scientific perspective, the most fascinating aspect of this peptide is its potential ability to regulate reproductive function by acting on the gonadotropin-releasing hormone (GnRH) pathway. Researchers hope to discover Kisspeptin-10’s potential in various physiological and pathological settings by elucidating the complex processes behind its activities.
Kisspeptin-10 Peptide: Mechanism of Action
In animals where it is studied, GPR54, also known as the KISS1 receptor (KISS1R), is thought to serve a crucial function as a GnRH receptor and is crucial for the beginning of puberty. Kisspeptin-10 peptide binding to GPR54 receptors may stimulate the reproductive axis by promoting GnRH and gonadotropin neuron production. Kisspeptin-10 seems to impact the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by activating approximately 85% of GnRH neurons in the central nervous system. [i]
The KISS1 gene encodes the 54-amino-acid peptide known as Kisspeptin-10. Additionally, it seems that Kisspeptin-10 peptide segments 13 and 14 may have biological activity towards GPR54. These shorter peptides may bind to GPR54 receptors with a lesser affinity, but they still seem to be able to activate calcium mobilization, arachidonic acid release, and extracellular protein kinase activation. [i]
These changes may modulate gonadotropin release by depolarizing GnRH neurons, which may, in turn, depolarize Kisspeptin-10 neurons. [ii]
The Discovery of the Kisspeptin-10 Peptide
An important step forward was taken in the middle of the 1990s when a cancer cell’s integration with chromosome 6 appeared to restrict the creation of metastasis and the spread of cancer cells. [iii] This region of DNA eventually became known as the KISS1 gene.
Kisspeptin-10 peptide seems to operate as a ligand for the G-protein coupled receptor 54 (GPR54), and by the middle of the 2000s, multiple separate studies had suggested its possible implications in hypogonadotropic hypogonadism. [iv]
Studies on the Peptide Kisspeptin-10 Peptide
Gonadotropin-Releasing Hormone and the Kisspeptin-10 Peptide
Hypothalamic GnRH neurons have been hypothesized to be responsible for synthesizing and secretion of Gonadotropin-releasing hormone (GnRH). This neuropeptide may have a key regulatory role in the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland, suggesting that it is the first hormone produced within the hypothalamic-pituitary-gonadal (HPG) axis. It is widely considered that gonadotropin-releasing hormone (GnRH) may play a critical role in puberty by coordinating the development of gametes within the reproductive system. It seems that the reproductive system is significantly impacted by the fine-tuning of GnRH release and its downstream effects.
A systematic literature review, including works published between 1999 and 2016, was done as part of a 2017 [v] research. Combined information from these studies strongly suggests that the Kisspeptin-10 system may play an important part in puberty onset and maintenance through the GPR54 receptor and the KISS1 gene and its gene products. Possible aberrations in the KISS1 and GPR54 system have been linked to the occurrence of reproductive disorders like hypogonadotropic hypogonadism (HH) and polycystic ovary syndrome (PCOS), as suggested by some studies performed on animal models exhibiting features similar to HH and PCOS.
Testosterone Synthesis and the Kisspeptide-10 Peptide
Studies suggest the Kisspeptin-10 peptide may likely affect testosterone levels by regulating the concentrations of LH and FSH in the blood. Kisspeptin-10 peptide seems to have a sex-specific effect on testosterone levels. While presenting peptides to male test models seemed to enhance testosterone levels, no such impact was seen in female models. Notably, in a research study with six male subjects, plasma testosterone levels seemed to increase significantly, doubling only 90 minutes after receiving a derivative of Kisspeptin-10. [vi]
The fact that the Kisspeptin-10 peptide seems to affect the pulsatile release of LH in male test subjects suggests it may regulate the regular symphony of sex hormone production. Kisspeptin-10 was suggested by research to cause a fast and concentration-dependent spike in blood LH levels in another investigation, including healthy male models, with a concomitant increase in testosterone levels. Researchers hypothesize that the Kisspeptin-10 peptide may achieve this result by stimulating LH release in a pulsatile manner.
Higher quantities of the Kisspeptin-10 peptide seem to generate indistinguishable, continuous LH release rather than discrete pulsation. Researchers speculate that “Kisspeptin-10 boluses potently evoke LH secretion […]” and testosterone, LH pulse frequency, and pulse size were all elevated with continuous infusion.” Applications for Kisspeptin analogs such as LH and, by extension, testosterone secretion regulators have been suggested. [vii]
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[i] Rønnekleiv, O. K., & Kelly, M. J. (2013). Kisspeptin-10 excitation of GnRH neurons. Advances in experimental medicine and biology, 784, 113–131. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019505/
[ii] Tng E. L. (2015). Kisspeptin-10 signalling and its roles in humans. Singapore medical journal, 56(12), 649–656. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678402/
[iii] Pasquier, J., Kamech, N., Lafont, A., Vaudry, H., Rousseau, K., & Dufour, S. (2014). MOLECULAR EVOLUTION OF GPCRS: Kisspeptin-10/Kisspeptin-10 receptors, Journal of Molecular Endocrinology, 52(3), T101-T117. https://jme.bioscientifica.com/view/journals/jme/52/3/T101.xml
[iv] Messager, S., Chatzidaki, E. E., Ma, D., Hendrick, A. G., Zahn, D., Dixon, J., Thresher, R. R., Malinge, I., Lomet, D., Carlton, M. B., Colledge, W. H., Caraty, A., & Aparicio, S. A. (2005). Kisspeptin-10 directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proceedings of the National Academy of Sciences of the United States of America, 102(5), 1761–1766. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545088/
[v] Zeydabadi Nejad, S., Ramezani Tehrani, F., & Zadeh-Vakili, A. (2017). The Role of Kisspeptin in Female Reproduction. International journal of endocrinology and metabolism, 15(3), e44337. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702467/
[vi] W. S. Dhillo et al., “Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males,” J. Clin. Endocrinol. Metab., vol. 90, no. 12, pp. 6609–6615, Dec. 2005, doi: 10.1210/jc.2005-1468. https://academic.oup.com/jcem/article/90/12/6609/2837183
[vii] George JT, Veldhuis JD, Roseweir AK, Newton CL, Faccenda E, Millar RP, Anderson RA. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab. 2011 Aug;96(8):E1228-36. doi: 10.1210/jc.2011-0089. Epub 2011 Jun 1. PMID: 21632807; PMCID: PMC3380939. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380939/