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Research on the Hypothalamus and Kisspeptin-10 Peptide

Studies suggest that Kisspeptin-10, also known as Metastin, is a peptide obtained from the cleavage of Kisspeptin-54. Kisspeptin-54, in turn, is synthesized from a precursor polypeptide encoded by the KISS1 gene.  

Research on the Hypothalamus and Kisspeptin-10 Peptide
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First Published Dec 7, 2023, 4:05 PM IST

Studies suggest that Kisspeptin-10, also known as Metastin, is a peptide obtained from the cleavage of Kisspeptin-54. Kisspeptin-54, in turn, is synthesized from a precursor polypeptide encoded by the KISS1 gene. Hypothalamic cells in the brain's central nervous system are responsible for the normal production of kisspeptins. Research suggests the kisspeptin (KISS1) gene that may be identified in those cells produces a 145-amino acid polypeptide that, once processed, can create several different kisspeptin sequences.

The sequence of Kisspeptin-10 is Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH2, and it is made up of a total of ten different amino acids. It has the same C-terminal decapeptide sequence as the other processed kisspeptin sequences, and this sequence is referred to as RFAmide (arginine-amidated phenylalanine). Researchers have speculated that Kisspeptin-10 has a shorter half-life and a quicker commencement of potential action, although its intrinsic bioactivity is considered to be comparable to longer Kisspeptin fragments. This is one of its distinguishing characteristics. 

Kisspeptin-10 and the Gonadotropic Axis

It would seem that Kisspeptin-10 might significantly function in the GnRH-producing hypothalamus cells. The possible impact of Kisspeptin-10 (KP-10) on gene expression was investigated by researchers using a variety of hypothalamic cell lines. They hypothesized that in mHypoA-50 AVPV cells, Kisspeptin-10 may raise levels of Kiss-1 mRNA and Kisspeptin protein, potentially without affecting GnRH expression. Findings implied that stimulation with Kisspeptin-10 may cause an upregulation of the expression of GnRH and Kisspeptin genes in mHypoA-55 ARC cells. In addition to this, Kisspeptin-10 suggested signs of increasing c-Fos protein levels, which is indicative of the presence of possible neuronal activity in both cell lines. Primary cultures of fetal rat neural cells appeared to have exhibited observable responses comparable to those described above. 

Data suggests that Kisspeptin-10 may induce gonadotropin-releasing hormone (GnRH) secretion in prepubescent and pubescent animals. When exposed to Kisspeptin-10, researchers speculated that there seemed to be a major modification of the initial Kisspeptin and neurokinin B (NKB) signaling pathways. There is a possibility that Kisspeptin-10 may interact with the release of GnRH via NKB neurons and Kisspeptin neurons. In addition, researchers hypothesize that there may be "a parallel increase in the release of Kisspeptin and GnRH during puberty." However, there was no indication that the peptide may initiate pubescence in the test subjects. 

Kisspeptin-10 and Neurons

Cholinergic neurons might be harmed if amyloid-beta (Abeta) and alpha-synuclein (alpha-syn) were to reside in these cells. Despite this, researchers speculate that Kisspeptin-10 may be able to attach to A outside of cells, and so may be able to reduce the toxicity of A. 


The findings of the researchers also suggest that "The KP peptides hindered the neurotoxicity of A, PrP, and IAPP peptides via a measure that could not be intercepted by kisspeptin-receptor (GPR-54) or neuropeptide FF (NPFF) receptor antagonists." Other studies have also postulated that Kisspeptin-10 could similarly alleviate the toxicity generated by -syn in cholinergic neurons. Their reasoning is based on similarities between the non-amyloid- component (NAC) of -syn and the C- terminus of A. They performed studies utilizing cholinergic cells and suggested that high concentrations of Kisspeptin-10 may raise toxicity, while low concentrations may lower both wild-type and E46K mutant-syn-induced toxicity. These comments were based on the results of the research. These results were validated by the computational study, which suggested that a potentially positive interaction between Kisspeptin-10 and the C-terminal residues of -syn may exist. Molecular dynamics simulations also implied that the Kisspeptin-10-a-syn complexes may have high stability. 


Scientists have continued their investigation into this subject, notably focusing on whether or not the activation of GPR54, the receptor for the Kisspeptin gene, is required for the Kisspeptin-10 binding potential to the C-terminal pockets of -syn. ChAT-positive SH-SY5Y neurons were generated to overexpress wild-type or E46K mutant-syn to test this. Flow cytometry and immunocytochemistry were then used to analyze the possible influence of Kisspeptin-10 on -syn-induced neuronal death. Wild- type and E46K mutant-syn expression in cholinergic neurons was speculated to produce apoptosis and mitochondrial damage. Kisspeptin-10 seemed to mitigate both of these effects. Interestingly, the apparent neuroprotective potential of Kisspeptin-10 was not altered by concurrent presentation with a GPR54 antagonist, Kisspeptin-234 (KP-234). This finding suggests that activation of GPR54 may not be necessary for Kisspeptin-10's impact. In addition, the researchers noted that Kisspeptin-10 may have decreased the immunoreactivity of -syn and choline acetyltransferase (ChAT) in neurons that overexpressed wild-type and E46K mutant -syn. 

Kisspeptin-10 and Stimui

Researchers have examined the levels of dopamine (DA), norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT), dihydroxyphenylacetic acid (DOPAC), and 5- hydroxy indole acetic acid (5-HIIA) in hypothalamic cells (Hypo-E22) to investigate the potential metabolic and orexigenic action of Kisspeptin-10. The findings implied that Hypo-E22 cells tolerate Kisspeptin-10, which may independently boost NPY gene expression, whereas BDNF expression looked repressed. In addition, it seemed that levels of 5-HT and DA were decreased by Kisspeptin-10, whereas levels of NE were speculated to have remained unaltered. Increased ratios of DOPAC/DA and 5-HIIA/5- HT were compatible with the suggested reduction in dopamine and serotonin (5-HT and DA), both produced by the peptide. The orexigenic potential of Kisspeptin-10 may be supported by the apparent increase in NPY expression and the reduction in BDNF and 5-HT activity. 

Conclusion

In conclusion, compared to lengthier Kisspeptin fragments, Kisspeptin-10, produced from the cleavage of Kisspeptin-54, may have different properties. Research conducted in vitro has given insight into the possible impacts that it might have on the gonadotropic axis, cholinergic neurons, and orexigenic stimuli. It would suggest that Kisspeptin-10 may modulate gene expression and protein levels, which might affect neuronal activity and GnRH release. In addition, it suggests potential in reducing the toxicity generated in cholinergic neurons by amyloid- and -synuclein. It was purported that the neuroprotective potential of the peptide may be detected even in the absence of GPR54 activation, suggesting that other mechanisms may be at work. In addition, research suggests that Kisspeptin-10 may affect the expression of genes as well as the levels of neurotransmitters as a result of its orexigenic potential. 

Scientists interested in peptides for sale online should navigate to the Core Peptides website. Please note that none of the substances mentioned in this article have been approved for human consumption. 

References

[i] Kotani, M., Detheux, M., Vandenbogaerde, A., Communi, D., Vanderwinden, J. M., Le Poul, E., Brézillon, S., Tyldesley, R., Suarez-Huerta, N., Vandeput, F., Blanpain, C., Schiffmann, S. N., Vassart, G., & Parmentier, M. (2001). The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. The Journal of biological chemistry, 276(37), 34631–34636. 

[ii] Kanasaki, H., Tumurbaatar, T., Tumurgan, Z., Oride, A., Okada, H., & Kyo, S. (2021). Mutual Interactions Between GnRH and Kisspeptin in GnRH- and Kiss-1-Expressing Immortalized Hypothalamic Cell Models. Reproductive sciences (Thousand Oaks, Calif.), 28(12), 3380–3389. 

[iii] Garcia, J. P., Keen, K. L., Seminara, S. B., & Terasawa, E. (2019). Role of Kisspeptin and NKB in Puberty in Nonhuman Primates: Sex Differences. Seminars in reproductive medicine, 37(2), 47–55. 

[iv] Guo, L., Xu, H., Li, Y., Liu, H., Zhao, J., Lu, W., & Wang, J. (2022). Kisspeptin-10 Promotes Progesterone Synthesis in Bovine Ovarian Granulosa Cells via Downregulation of microRNA-1246. Genes, 13(2), 298. 

[v] Milton NG, Chilumuri A, Rocha-Ferreira E, Nercessian AN, Ashioti M. Kisspeptin prevention of amyloid-β peptide neurotoxicity in vitro. ACS Chem Neurosci. 2012 Sep 19;3(9):706-19. doi: 10.1021/cn300045d. Epub 2012 May 30. PMID: 23019497; PMCID: PMC3447396.


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