From KISS1 to Kisspeptins: An Historical Perspective and Suggested Nomenclature

Abstract

The cancer suppressor gene, KISS1, was initially described as having an important role in inhibiting cancer metastasis. Since then, KISS1 and its receptor, KISS1R, have been shown to play a key role in controlling the onset of puberty of reproductive physiology in the human and other species. Recent studies have also linked KISS1/KISS1R/kisspeptin to other processes, such as vasoconstriction, aging, adipocyte physiology, and perhaps as a molecular conduit linking metabolism and reproduction. This article highlights the history of KISS1/KISS1R/kisspeptin biology and proposes a consensus for nomenclature of the key molecules in this signaling pathway.

1.0 Introduction

The cancer suppressor gene, KISS1, may have been named with a bit of whimsy, to ensure everyone knew (or might guess) where it was discovered— in Hershey, Pennsylvania, of course, the home of the famous Hershey Kisses (26, 27)! However, the impact of the discovery of the KISS1 gene now reaches far beyond the chocolate morsel. The KISS1 gene encodes for a hydrophobic 145 amino acid protein (1, 24, 40), which can be cleaved into a 54 amino acid protein, originally called metastin for its ability to inhibit cancer metastasis (40). Both the 145 and 54 amino acid proteins contain a sequence that predisposes the proteins for ubiquitination and proteosome degradation, suggesting that they may have a short half-life (14). The 54 amino acid metastin and the shorter peptides (10, 13 and 14 amino acids long) were collectively named kisspeptins, because they are the proteolytic bi-products of a common precursor protein encoded by the KISS1 gene (24). It is unclear how the shorter peptides are processed from the larger peptide or whether the shorter peptides are bio-available (40). Nevertheless, when isolated, each of these peptides has a common C-terminal amidation site that leads to strong binding with their receptor (6, 25, 36, 40, 58). The larger peptide comprises some variability among species, whereas the 10 amino acid C-terminus peptide is well conserved and binds to and activates KISS1R (24, 26, 36, 40). KISS1 and KISS1R genes are both expressed in various tissues, including the placenta, brain, pituitary, gonads, liver, pancreas, intestines, aorta, coronary artery and umbilical vein (26, 34, 36, 40, 45).

2.0 Discovery

KISS1 was discovered in 1996 (26). The gene coding for the kisspeptin receptor, KISS1R, which shares a modest sequence identity with the gene coding for galanin receptor 2, was described in 1999 (25); however, it was not until 2003 that the receptor caught the attention of reproductive physiologists. Scientists became familiar with KISS1R when it was known simply as the orphan G protein-coupled receptor (GPR) 54 or as code name “Harry Potter” by investigators at Paradigm Therapeutics, who were the first to disrupt its expression in mice (49).

In 2003, reports by two independent groups brought kisspeptin-KISS1R signaling to the immediate and rapt attention of reproductive biologists. Within months of one another, Nicolas De Roux and his colleagues and Stephanie Seminara and her collaborators described the genetic basis of the hypothalamic hypogonadism found in some of their patients who failed to show normal sexual maturation. Their genetic analysis revealed that mutations in KISS1R were associated with impaired pubertal maturation (8, 49). This mutation was initially described in several consanguineous families, and a few other non-related patients; and later, the phenotype was recapitulated in mice that have deletional mutations of Kiss1r, lending credence to the argument that this was indeed the causal agent (11, 49). The discovery of a single receptor gene mutation that has profound effects upon the activation of pubertal maturation without other discernable effects (10, 11, 49) kindled enthusiasm to revisit an old unresolved problem— how the hypothalamic-pituitary-gonadal axis is activated at the time of puberty. Fanning this excitement were two other important corroborating discoveries— first, mice with deletional mutations in Kiss1 itself (coding for the Kiss1r ligand) fail to undergo normal pubertal maturation and second, humans with an “activating” mutation of KISS1R develop precocious puberty (7, 59).

3.0 Role of Kisspeptin and KISS1 Receptor

Since the discovery of KISS1 and KISS1R, numerous reports about kisspeptin signaling have appeared, including some that extend well beyond the realm of cancer biology and the physiology of puberty. These findings have been recently reviewed by Mead (33), Seminara (51) and Popa (43), and several of these topics will be discussed in further detail in this issue of Peptides and thus mentioned only briefly here.

The KISS1 gene was originally found to inhibit metastasis of cancer cells (26, 27) and later discovered to be expressed abundantly in the placenta (1). Since then, it has been shown that KISS1 gene expression down-regulates the activity of matrix metalloproteinases (1, 16, 62), which is thought to be the mechanism that KISS1 suppresses cancer metastasis and may also have a role in placentation and perhaps the pathogenesis of preeclampsia (1, 19).

In the brain of rodents, Kiss1 is located in the anteroventral periventricular nucleus (AVPV), arcuate nucleus (Arc), anterodorsal preoptic nucleus (ADP), amygdala, and bed nucleus of the stria terminalis (BnST) (12, 38, 55), and Kiss1 (or the kisspeptin protein) has been identified in homologous areas in fish (21), sheep (35) and monkeys (52). Furthermore, the majority of GnRH neurons express the kisspeptin receptor, Kiss1r (18, 35, 41). Miniscule molar amounts of kisspeptin (in the femptomole range) can induce robust GnRH/LH secretion in a wide range of species, including rodents, primates, cattle and fish (9, 12, 18, 20, 29, 32, 35, 37, 52, 60), and kisspeptins can directly (and perhaps indirectly) stimulate GnRH neurons (13, 42). Levels of Kiss1 mRNA increase in the AVPV in association with the onset of puberty (13), and GnRH neurons become more sensitive to the effects of kisspeptin, which may reflect an increase in the number of Kiss1/GnRH appositions (5, 13) or an undefined “maturation” of the Kiss1r that gates signal transduction (13). Finally, the administration of kisspeptins can stimulate GnRH/LH secretion in prepubertal primates and even advance pubertal onset in some species (20, 29, 37, 50).

Gonadal sex steroids differentially regulate Kiss1 mRNA expression in AVPV and Arc of the hypothalamus (38, 55, 56) and induce Kiss1 expression in pituitary gonadotropes (45), likely via the estrogen receptor (ER) alpha (45, 55). However, recent reports suggest that in the hypothalamus, ER beta and the progesterone receptor may also influence whether the effect of estradiol on Kiss1 expression is stimulatory or inhibitory (47). The expression of Kiss1 in the AVPV of the rodent is sexually differentiated, with females showing greater expression than males (5, 22). Similar results have been demonstrated in some species of fish, but in at least one reported instance, males have greater Kiss1 expression than females (21). In female rodents, the sexually dimorphic pattern of Kiss1 expression can be reversed by exposure to androgens during the perinatal critical period (22). Kisspeptin-Kiss1r signaling seems to be critical for the preovulatory LH surge with Kiss1 mRNA expression being highest prior to the LH surge in the AVPV (57) [and the ovary as well (3)]. Moreover, antiserum to kisspeptin can block the LH surge in the rat, arguing for the importance of kisspeptin signaling for generating the preovulatory GnRH/LH surge (23). Despite this inference, it would appear that kisspeptin-GnRH signaling is not the entire story, since mice that are null for Kiss1r retain the ability to show a GnRH/LH surge in response to an estradiol challenge (10). Redundant pathways may compensate in the absence of Kiss1r (when gonadal sex steroids are replaced) or perhaps compensatory mechanisms develop to “correct” the genetic lesion (10). The expression of Kiss1 mRNA is down-regulated in both the ARC and AVPV during lactation (61), and Kiss1 expression is seasonally regulated in some mammals (31, 44) and fish (21).

Additionally, Kiss1 mRNA is expressed in the alpha and beta cells of the cells of pancreatic Islets of Langerhan (15). Although the effect of kisspeptins upon glucose mediated insulin secretion in normal animals is equivocal, in diabetic rats, kisspeptin can apparently rescue gonadotropin secretion (4, 15, 53). Kiss1 mRNA in the Arc is also decreased in leptin-deficient male mice and can be partially restored with leptin treatment (56). In addition, injections of kisspeptin have been shown to stimulate gonadotropin secretion in rodents treated with leptin antibodies (4), suggesting that kisspeptin may be involved in leptin signaling in the neuroendocrine reproductive axis. Ghrelin has been shown to have a countervailing effect on the ability of kisspeptin to regulate reproductive function (30). Another recent report has shown that kisspeptin signaling can affect vasoconstriction (34), and Kiss1 mRNA expression is regulated in adipose tissue (2), which suggests that kisspeptin could serve as a molecular link between metabolism and reproduction.

4.0 Nomenclature

With the broad interest in kisspeptin-KISS1R signaling, it is important to develop more consistency in nomenclature of the key molecules. Several terms that refer to kisspeptin and kisspeptin receptor have been used over the past 5 years. For example, in reference to just the receptor, one can find AXOR12, hOT7T175, GPR54, KISS1R, KiSS1 and the metastin receptor (24, 25, 36, 40, 46). Further confusion results when distinguishing among the gene, the mRNA, and the protein, and when differentiating among species.

The kisspeptin protein was originally named metastin (specifically referring to one of the peptide products of the gene); however, the term ‘kisspeptin’ has come into more widespread and general use. We recommend that ‘kisspeptin’ be used in reference to the protein product(s) of the gene, because the physiological significance of the protein extends far beyond its role as “suppressor” of metastasis. We also suggest that metastin be used only in references to human kisspeptin-54, as this is where it was discovered and there are considerable sequence differences between the human 54 amino acid peptide and Kp-54 from other species (24, 26, 36, 40). Furthermore, the use of the term metastin should be limited to cancer biology, where its name has direct relevance.

The Human Genome Organization Gene Nomenclature Committee (HGNC) has proposed the use of KISS1 as the symbol for the kisspeptin gene (http://www.genenames.org/data/hgnc_data.php?hgnc_id=6341). With respect to other species, the international committees that were established to standardize the nomenclature for the mouse and rat genomes recommend that when possible, the same symbol be used for orthologs among human, mouse and rat, except that the symbol should begin with an upper case letter, followed by all lowercase letters / numbers (http://www.informatics.jax.org/mgihome/nomen/gene.shtml). In addition, they recommend that gene symbols be italicized. Based on these recommendations, we suggest that KISS1 be used to represent the human kisspeptin gene and Kiss1 to represent non-human kisspeptin genes. [The use of hyphenation (Kiss-1) is expressly discouraged because various search engines handle the hyphen differently and this can significantly affect search outcomes.] Furthermore, we suggest that non-italicized versions of the gene nomenclature be used to refer to the protein products of KISS1 (KISS1 for human and Kiss1 for other species)—but spelling out ‘kisspeptin’ would always appropriate, and is an easy way to denote both the protein product of KISS1 and its various peptide products collectively.

Distinguishing between the peptide products that are cleaved from the 145 amino acid protein requires clarity. Some reports have made reference to the peptide products as kisspeptin −54, -14, -13, and -10, differentiating by peptide length (54 amino acids, 14 amino acids etc.). Others refer to the numerical sequence of amino acids that are cleaved from the original 145 amino acid pre-protein; for example, kisspeptin (68-121) or kisspeptin (112-121) refers to amino acids 68-121 or 112-121 of the original 145 amino acid peptide, which would also represent Kp-54 or Kp-10. Furthermore, others have made reference to kisspeptin-1 (68-121), which was likely done just in case another KISS gene were to be discovered. However, this nomenclature is infrequently used, and certainly a new system could be established if another KISS gene were discovered.

We know that each of the kisspeptin fragments is the proteolytic product of the common precursor and contains the all important C-terminal amide sequence. Since most reports distinguish between bioactive kisspeptin fragments based on size, it seems sensible to refer to their size, and abbreviate kisspeptin as KP or Kp. Thus, the abbreviation for the 10-amino acid kisspeptin peptide would be KP-10 for the human and Kp-10 for other species. A collection of various usages of KISS1/KISS1R and kisspeptins as well as our suggestions for simplified use is summarized in Tables 1 and 2.

Table 1.

Current and Recommended Symbols for the Kisspeptin Gene and Protein

Species	Current Terminology		Recommended Terminology
	Gene/mRNA	Peptide	Gene/mRNA	Peptide
Rodent and other non-human species	KiSS-1 KiSS1 Kiss-1 Kiss1 (typically italicized for the gene and not for mRNA) MGI format: Kiss1	Mature Peptide: metastin kisspeptin kisspeptin-54 KiSS-1 peptide KiSS-1 protein	Kiss1/Kiss1 mRNA	Mature Peptide: kisspeptin Kiss1
		Bioactive Fragments: kisspeptin-145, -14, -13, -10 Kp-145, -14, -13, -10 kisspeptin-1 (68-121) kisspeptin/metastin (112-121) KiSS-1 peptide KiSS-1 protein		Bioactive Fragments: kisspeptin-fragment length (e.g. Kisspeptin-10) Kp-fragment length (e.g., Kp-10)
Human	KiSS-1 KiSS1 (typically italicized for the gene and not for mRNA) HGNC symbol: KISS1	Mature Peptide: metastin kisspeptin KiSS-1	KISS1/KISS1 mRNA	Mature Peptide: Kisspeptin KISS1
		Bioactive Fragments: Kisspeptin-145, -14, -13, -10 Kp-145, -14, -13, -10 Human metastin 45-54		Bioactive Fragments: kisspeptin-fragment length (e.g. Kisspeptin-10) KP-fragment length (e.g., KP-10)

Table 2.

Current and Recommended Terminology for the Kisspeptin Receptor Gene and Protein

Species	Current Terminology		Recommended Terminology
	Gene/mRNA	Peptide	Gene/mRNA	Peptide
Rodent and other non-human species	GPR54 Gpr54 MGI format: Kiss1r	GPR54 Kiss1R	Kiss1r/Kiss1r mRNA	kisspeptin (or Kiss1) receptor Kiss1r
Human	AXOR12 HOT7T175 GPR54 KiSS1R HGNC format: KISS1R	GPR54 KiSS1 (GPR54)	KISS1R/KISS1R mRNA	kisspeptin (or KISS1) receptor KISS1R

In databases such as mouse genome informatics (MGI), GPR54 was noted as the official name for the kisspeptin receptor from August 2001 until February 2006, after which the term Kiss1r was assigned, because the once orphaned receptor was no longer without a ligand. Likewise, HGNC recommends the use of KISS1R for the human kisspeptin receptor gene. If we follow those recommendations, the nonhuman Gpr54 gene or mRNA should be referred to as Kiss1r, and the human gene or mRNA as KISS1R (again a matter of case to distinguish between the two). The same convention should then be applied to the receptor protein references -- Kiss1r should be used for the nonhuman receptor protein and KISS1R for the human receptor protein. It should be noted that the International Union of Pharmacology (IUPHAR) does not include an ‘R’ in receptor protein abbreviations and refers to kisspeptin receptor protein as KiSS1. We believe there are good reasons for not following the IUPHAR convention in this case. First, using a lower/upper case ‘i’ as the only means to differentiate between the ligand and the receptor will cause considerable confusion. Second, most prior reports have used KiSS1 to refer to the KISS1 gene product (i.e. the ligand, not the receptor), thus adding to the confusion. Third, there is no consistent way to distinguish the human from the nonhuman form of the peptide, since both would have to be KiSS1. We therefore argue that keeping the ‘R’ in KISS1R protein references allows for greater ease in distinguishing the peptide from its receptor and makes its designation consistent with that of its gene (KISS1R).

5.0 Summary

The discovery of the KISS1 and KISS1R genes has revealed a number of exciting discoveries in cancer biology and reproductive endocrinology. Recent studies have implicated these genes in aging and menopause (48), adipocyte physiology (2), as a molecular link between metabolism and reproduction (17), and perhaps as a target for the action of environmental estrogens on reproduction (39). This issue of Peptides will serve as collection of these critical new findings and perhaps serve as a springboard for ideas and collaborative efforts in the future. Who knew that a little KISS from Hershey PA would leave such lingering sweetness?