Kisspeptin (formerly known as
Metastin), the product of the gene is a G-protein coupled receptor
ligandIn biochemistry and pharmacology, a ligand is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as...
for
GPR54The KiSS1-derived peptide receptor is a G protein-coupled receptor which binds the peptide hormone kisspeptin . Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues...
.
Kiss1 was originally identified as a human
metastasis suppressorA metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. These proteins are different from ones that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals, including...
gene that has the ability to suppress
melanomaMelanoma is a malignant tumor of melanocytes which are found predominantly in skin but also in the bowel and the eye . It is one of the less common types of skin cancer but causes the majority of skin cancer related deaths. Melanocytes are normally present in skin, being responsible for the...
and
breast cancerBreast cancer is a cancer that starts in the breast, usually in the inner lining of the milk ducts or lobules. There are different types of breast cancer, with different stages , aggressiveness, and genetic makeup. With best treatment, 10-year disease-free survival varies from 98% to 10%...
metastasisMetastasis , or metastatic disease, sometimes abbreviated mets, is the spread of a disease from one organ or part to another non-adjacent organ or part...
. It is recently become clear that kisspeptin-GPR54 signaling has an important role in initiating
GnRHGonadotropin-releasing hormone , also known as Luteinizing-hormone releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of FSH and LH from the anterior pituitary...
secretion at puberty, the extent of which is an area of ongoing research.
The
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
encoded by this gene is a
metastasisMetastasis , or metastatic disease, sometimes abbreviated mets, is the spread of a disease from one organ or part to another non-adjacent organ or part...
suppressor of
melanomaMelanoma is a malignant tumor of melanocytes which are found predominantly in skin but also in the bowel and the eye . It is one of the less common types of skin cancer but causes the majority of skin cancer related deaths. Melanocytes are normally present in skin, being responsible for the...
s and
breast cancerBreast cancer is a cancer that starts in the breast, usually in the inner lining of the milk ducts or lobules. There are different types of breast cancer, with different stages , aggressiveness, and genetic makeup. With best treatment, 10-year disease-free survival varies from 98% to 10%...
s without affecting tumorigenicity.
Kisspeptin (formerly known as
Metastin), the product of the gene is a G-protein coupled receptor
ligandIn biochemistry and pharmacology, a ligand is a substance that is able to bind to and form a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as...
for
GPR54The KiSS1-derived peptide receptor is a G protein-coupled receptor which binds the peptide hormone kisspeptin . Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues...
.
Kiss1 was originally identified as a human
metastasis suppressorA metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. These proteins are different from ones that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals, including...
gene that has the ability to suppress
melanomaMelanoma is a malignant tumor of melanocytes which are found predominantly in skin but also in the bowel and the eye . It is one of the less common types of skin cancer but causes the majority of skin cancer related deaths. Melanocytes are normally present in skin, being responsible for the...
and
breast cancerBreast cancer is a cancer that starts in the breast, usually in the inner lining of the milk ducts or lobules. There are different types of breast cancer, with different stages , aggressiveness, and genetic makeup. With best treatment, 10-year disease-free survival varies from 98% to 10%...
metastasisMetastasis , or metastatic disease, sometimes abbreviated mets, is the spread of a disease from one organ or part to another non-adjacent organ or part...
. It is recently become clear that kisspeptin-GPR54 signaling has an important role in initiating
GnRHGonadotropin-releasing hormone , also known as Luteinizing-hormone releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of FSH and LH from the anterior pituitary...
secretion at puberty, the extent of which is an area of ongoing research.
Function
The
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
encoded by this gene is a
metastasisMetastasis , or metastatic disease, sometimes abbreviated mets, is the spread of a disease from one organ or part to another non-adjacent organ or part...
suppressor of
melanomaMelanoma is a malignant tumor of melanocytes which are found predominantly in skin but also in the bowel and the eye . It is one of the less common types of skin cancer but causes the majority of skin cancer related deaths. Melanocytes are normally present in skin, being responsible for the...
s and
breast cancerBreast cancer is a cancer that starts in the breast, usually in the inner lining of the milk ducts or lobules. There are different types of breast cancer, with different stages , aggressiveness, and genetic makeup. With best treatment, 10-year disease-free survival varies from 98% to 10%...
s without affecting tumorigenicity. The encoded protein may function to inhibit
chemotaxisChemotaxis is the phenomenon in which bodily cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules, or...
and invasion, attenuating metastasis in malignant melanomas. Studies suggest a putative role in the regulation of events downstream of cell-matrix adhesion, perhaps involving
cytoskeletalThe cytoskeleton is a cellular "scaffolding" or "skeleton" contained within the cytoplasm. The cytoskeleton is present in all cells; it was once thought this structure was unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
reorganization. A
polymorphismPolymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
in the terminal
exonAn exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule after either portions of a precursor RNA have been removed by cis-splicing or by two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA or...
of this
mRNAMessenger ribonucleic acid is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino...
results in two protein
isoformA protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single nucleotide polymorphisms or SNPs, small genetic...
s. An adenosine present at the polymorphic site represents the third position in a stop codon. When the
adenosineAdenosine is a nucleoside composed of a molecule of adenine attached to a ribose sugar molecule moiety via a β-N
9-glycosidic bond....
is absent, a downstream
stop codonIn the genetic code, a stop codon is a nucleotide triplet within messenger RNA that signals a termination of translation. Proteins are unique sequences of amino acids, and most codons in messenger RNA correspond to the addition of an amino acid to a growing protein chain — stop codons signal...
is utilized and the encoded protein extends for an additional seven amino acid residues.
Discovery
The
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
for kisspeptin, GPR54, was first identified as an orphan GPCR in rat in 1999. Following in 2001, a natural
ligandIn chemistry, a ligand is either an atom, ion, or molecule that binds to a central metal-atom to produce a coordination complex. The bonding between the metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The metal-ligand bonding ranges from covalent...
for GPR54 was discovered, which was the product of the Kiss1 gene, originally identified as a human
metastasisMetastasis , or metastatic disease, sometimes abbreviated mets, is the spread of a disease from one organ or part to another non-adjacent organ or part...
suppressor gene. Subsequent mutant studies led to the discovery that
LOF mutationsIn biology, a mutation is a randomly derived change to the nucleotide sequence of the genetic material of an organism.Mutations can be caused by copying errors in the genetic material during cell division, or by exposure to mutagens , or can be induced by the organism itself, by cellular processes...
in GPR54 causes failure to progress through
pubertyPuberty is the process of physical changes by which a child's body becomes an adult body capable of reproduction. Puberty is initiated by hormone signals from the brain to the gonads . In response, the gonads produce a variety of hormones that stimulate the growth, function, or transformation of...
in man, due to
hypogonadotropic hypogonadismHypogonadism is a medical term for a defect of the gonads that results in the underproduction of testosterone...
. Thus, it was concluded that Kisspeptin-GPR54 signaling is essential to initiate gonadotropin (LH/FSH) secretion at puberty.
The naming of the Kiss-1 gene and its product, kisspeptin, was made by the team of scientists who discovered the gene in
Hershey, Pennsylvania'Hershey is a census-designated place in Derry Township, Dauphin County in the U.S. Commonwealth of Pennsylvania. The community is located 14 miles east of Harrisburg and is part of the Harrisburg–Carlisle Metropolitan Statistical Area. Hershey has no legal status as an incorporated...
, famous for its chocolate "Kisses (Hershey's Kisses)".
Kisspeptin Neurons
Kisspeptin expressing neurons are located in:
- Anteroventral periventricular nucleus
The Periventricular nucleus is a composite structure of the hypothalamus.It should not be confused with the paraventricular nucleus....
(AVPV)
- Periventricular nucleus
The Periventricular nucleus is a composite structure of the hypothalamus.It should not be confused with the paraventricular nucleus....
(PVN)
- Anterodorsal preoptic nucleus
Preoptic nucleus can refer to:* Ventrolateral preoptic nucleus* Anterodorsal preoptic nucleus* Preoptic area...
(ADP)
- The arcuate nucleus
The arcuate nucleus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence...
(Arc)
Kisspeptin neurons reside in nuclei such as Arc and AVPV and send projections into the MPOA, where there is an abundance of GnRH cell bodies. This anatomical evidence suggests that Kisspeptin fibers appear in close anatomical relationship to GnRH (parvicellular) neurons. In fact, Kisspeptin appears to act directly on GnRH neurons (via GPR54) to stimulate the secretion of GnRH.
However, for kisspeptin to be involved in the regulation of GnRH release, it must also be sensitive to steroid levels within the circulation, as it has already been established that steroids produced by the gonads exert regulatory effects on FSH and LH levels through GnRH mediation. Therefore, there are (at least) two possible scenarios: That either kisspeptin neurons express steroid receptors (such as ERα, ERβ, and
ARThe androgen receptor , also known as NR3C4 , is a type of nuclear receptor which is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone...
) themselves, or they receive input from another mechanism about circulating steroid levels.
Coexpression imaging of Kiss-1 mRNA (using vector red) and steroid receptors determined that KiSS-1 neurons are direct target for the action of sex steroids in both the male and female mouse.
Role in Puberty
The following evidence has been cited to support a role for kisspeptin in puberty:
- Animals with LOF mutations and targeted deletions of GPR54 fail to progress through puberty as a result of hypogonadotropic * hypogonadism (HH).
- Activation of GnRH neurons is the key event that initiates the onset of puberty.
- Peripheral administration of kisspeptin to prepubertal, 25-day-old female rats stimulates LH secretion and induces ovulation in the rat.
- If kisspeptins trigger puberty onset, one would expect to see an increase in KiSS-1 mRNA and/or GPR54 mRNA expression during this time. RT-PCR essays and semiquantitative results support this hypothesis.
- The electrophysiologic response of GnRH neurons to kisspeptins appears to change dramatically over the course of puberty.
Mechanism of Action
Kisspeptin appears to directly activate GnRH neurons. Evidence for this involves the persistence of a neural response to kisspeptin levels even in the presence of TTX, a neurotoxin that blocks nerve signals.
- Gramicidin
Gramicidin is a heterogeneous mixture of six antibiotic compounds, Gramicidins A, B and C, making up 80%, 6%,and 14% respectively, all of which are obtained from the soil bacterial species Bacillus brevis and called collectively Gramicidin D. Gramicidin D are linear pentadecapeptides; that is...
-perforated patch recordings: approx. 30% of GnRH neurons respond to kisspeptin administration in prepubertal males, whereas 60% of GnRH neurons in adult mice responded.
- Because only adult mice respond to low doses of kisspeptin, it appears that GnRH neurons become developmentally activated by kisspeptin over the course of puberty.