Kisspepeptin-GPR54 signaling in the neuroendocrine reproductive axis
Section snippets
The discovery of kisspeptins and GPR54 and their role in puberty
Biologists studying cancer were the first to characterize the G protein-coupled receptor GPR54 and its ligand (Lee et al., 1999). Lee et al. discovered that the ligand for GPR54 was a product of the metastasis suppressor gene, Kiss1—the letters “ss” indicate a “suppressor sequence” and “Ki” was added as a prefix to reflect the fact that the molecule was discovered in Hershey, Pennsylvania, home of the Hershey chocolate “Kiss” (Lee et al., 1996, Lee and Welch, 1997). Because products of the Kiss1
Activational effects of Kisspeptins on GnRH neurons
Additional studies have revealed that kisspeptin-GPR54 signaling may serve a regulatory function in the neuroendocrine reproductive axis—beyond acting as a simple “gate” for the onset of puberty (Seminara et al., 2003, de Roux et al., 2003, Funes et al., 2003, Semple et al., 2005). First, it was discovered that centrally administered kisspeptins stimulate LH secretion via a GnRH-dependent mechanism (in both adult and prepubertal animals) (Gottsch et al., 2004, Thompson et al., 2004, Irwig et
Regulation of KiSS-1 and GPR54 mRNAs by sex steroids
Emerging evidence suggests that kisspeptin-GPR54 signaling serves as an afferent stimulatory input to GnRH neurons. However, the Kiss1 and GPR54 genes may be targets for regulation by sex steroids as part of the circuitry regulating the HPG axis. Navarro et al. (2004a) and Irwig et al. (2004) have provided evidence that KiSS-1- and GPR54-expressing neurons are targets for regulation by sex steroids. These teams have suggested that sex steroids estrogen (E) and testosterone (T) feed back to
Beyond reproductive neuroendocrinology
It is clear that kisspeptpin-GPR54 signaling is a critical component for normal reproductive function. Yet, there remain many unanswered questions in this new field of ‘kisspeptinology.’ GPR54 mRNA is expressed in other regions of the body, besides the brain (Lee et al., 1999, Muir et al., 2001, Clements et al., 2001, Kotani et al., 2001, Ohtaki et al., 2001); yet, we have no clue about its physiological relevance in these areas. Furthermore, most G protein-coupled receptors have several
Looking ahead
Finally, what lies ahead for investigations of kisspeptin-GPR54 signaling? First, the anti-metastatic properties of kisspeptin will continue to be investigated. New developments in this arena could provide insight concerning the molecular signals that cause cancers in situ to become metastatic and thereby render clues about strategies for its treatment. Second, learning more about the role of kisspeptins that are produced by the placenta may help us to understand the biology of implantation and
Acknowledgments
We are grateful to Jeremy Smith, Heather Dungan, Sonya Jakawich and Kathy Lee for their critical review of this manuscript. This work was supported by grants from the National Institutes of Health [R01 HD27142, SCCPRR (U54) HD12629, R01 DK61517] and the National Science Foundation (IBN 0110686).
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