Kisspepeptin-GPR54 signaling in the neuroendocrine reproductive axis

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Abstract

Kisspeptins, which are products of the Kiss1 gene, and their receptor, GPR54, have emerged as key players in the regulation of gonadotropin-releasing hormone (GnRH) secretion. Mutations or targeted deletions of GPR54 produce isolated hypogonadotropic hypogonadism in humans and mice, indicating that signaling through this receptor is a prerequisite for sexual maturation. Centrally administered kisspeptins stimulate GnRH and gonadotropin secretion in prepubertal and adult animals. Kisspeptin-expressing neurons are direct targets for the negative and positive feedback actions of sex steroids, which differentially regulate the expression of KiSS-1 mRNA in various regions of the forebrain. This review highlights what is currently known about kisspeptin-GPR54 signaling in the regulation of 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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