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Discovery of Potent Kisspeptin Antagonists Delineate Physiological Mechanisms of Gonadotropin Regulation
Open accessAbstract
Neurons that produce gonadotropin-releasing hormone (GnRH) are the final common pathway by which the brain regulates reproduction. GnRH neurons are regulated by an afferent network of kisspeptin-producing neurons. Kisspeptin binds to its cognate receptor on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion, thus gating down-stream events supporting reproduction. We have developed kisspeptin antagonists to facilitate the direct determination of the role of kisspeptin neurons in the neuroendocrine regulation of reproduction. In vitro and in vivo studies of analogues of kisspeptin-10 with amino substitutions have identified several potent and specific antagonists. A selected antagonist was shown to inhibit the firing of GnRH neurons in the brain of the mouse and to reduce pulsatile GnRH secretion in female pubertal monkeys; the later supporting a key role of kisspeptin in puberty onset. This analog also inhibited the kisspeptin-induced release of luteinizing hormone (LH) in rats and mice and blocked the postcastration rise in LH in sheep, rats, and mice, suggesting that kisspeptin neurons mediate the negative feedback effect of sex steroids on gonadotropin secretion in mammals. The development of kisspeptin antagonists provides a valuable tool for investigating the physiological and pathophysiological roles of kisspeptin in the regulation of reproduction and could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer.
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“Moreover, Roseweir et al. (2009) have demonstrated in several species that a kisspeptin antagonist blocks pulsatile GnRH/luteinizinghormone(LH)secretion.”
Background
Metadata
- Authors
- Roseweir, A. K., Kauffman, A. S., Smith, J. T., Guerriero, K. A., Morgan, K., Pielecka-Fortuna, J., Pineda, R., Gottsch, M. L., Tena-Sempere, M., Moenter, S. M., Terasawa, E., Clarke, I. J., Steiner, R. A., & Millar, R. P.
- Affiliations
- The Queen's Medical Research Institute (GB)
- University of Washington (US)
- Monash University (AU)
- University of Wisconsin–Madison (US)
- University of Virginia (US)
- Universidad de Córdoba (CO)
- University of Cape Town (ZA)
- Corresponding author
- Millar, Robert P.
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-03-25
- Volume
- 29
- Issue
- 12
- Pages
- 3920-3929
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3035813
- OpenAlex
- W2058657335
- Cited by
- 379
- References
- 53
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 7 · 2023: 9 · 2022: 14 · 2021: 18 · 2020: 17 · 2019: 14 · 2018: 26 · 2017: 25 · 2016: 20 · 2015: 34 · 2014: 39 · 2013: 39 · 2012: 29
- FWCI
- 39.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (5u54hd012629-31)
- U.S. Public Health Service (K99 056157)
- Medical Research Council (MC_EX_G0701682)
- National Health and Medical Research Council
- Instituto de Salud Carlos III (PI042082, RCMN C03/08, C03/08)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD 27142, R01-HD-11355, R01HD41469, R01HD015433, R01 HD15433, U54-HD-12629, U54HD-012629, K99HD056157, R01HD011355, R01HD027142, R01HD041469)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- kisspeptin, kisspeptin-10, GnRH neurons, gonadotropin regulation, puberty onset, luteinizing hormone secretion, neuroendocrine regulation of reproduction, precocious puberty, endometriosis, metastatic prostate cancer
- MeSH terms
- Receptors, Kisspeptin-1, Action Potentials, Animals, Brain, Castration, Cricetulus, Female, Cricetinae, Humans, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Macaca mulatta, Male, Peptides, Sheep, Structure-Activity Relationship, CHO Cells, Microdialysis, Tumor Suppressor Proteins, Receptors, G-Protein-Coupled, Mice, Rats, Kisspeptins, In Vitro Techniques
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