Kisspeptin
Encyclopedia
Kisspeptin the product of the gene , is a G-protein coupled receptor ligand
for GPR54
. Kiss1 was originally identified as a human metastasis suppressor
gene that has the ability to suppress melanoma
and breast cancer
metastasis
. It recently became clear that kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone
(GnRH) at puberty, the extent of which is an area of ongoing research.
s in length, which may be further truncated to 14, 13 or 10 amino acid carboxyl terminal fragments. These N-terminally truncated peptides are known as the kisspeptins and belong to a larger family of peptides known as RFamides which all share a common arginine
-phenylalanine
-NH2 motif at their C-terminus.
A polymorphism
in the terminal exon
of this mRNA
results in two protein isoform
s. An adenosine present at the polymorphic site represents the third position in a stop codon. When the adenosine is absent, a downstream stop codon
is utilized and the encoded protein extends for an additional seven amino acid residues.
this gene is transcribed within the hippocampal dentate gyrus. It is also transcribed in the vascular endothelium.
It is transcribed within the neocortex of the adrenal gland
with higher levels in foetal compared to adult tissues. Kisspeptin-54 can stimulate secretion of aldosterone
.
It is transcribed in the pancreas
within the islet cells and where it can stimulate release of insulin
.
Studies suggest a putative role in the regulation of events downstream of cell-matrix adhesion, perhaps involving cytoskeletal
reorganization.
encoded by this gene is a metastasis
suppressor of melanoma
s and breast cancer
s without affecting tumorigenicity. The encoded protein may function to inhibit chemotaxis
and invasion, attenuating metastasis in malignant melanomas.
It is found in atherosclerotic plaques of the coronary arteries.
for kisspeptin, GPR54, was first identified as an orphan GPCR in rat in 1999. Following in 2001, a natural ligand
for GPR54 was discovered, which was the product of the Kiss1 gene, originally identified as a human metastasis
suppressor gene. Subsequent mutant studies led to the discovery that LOF mutations
in GPR54 causes failure to progress through puberty
in man, due to hypogonadotropic hypogonadism
. Thus, it was concluded that Kisspeptin-GPR54 signaling is essential to initiate gonadotropin (LH/FSH) secretion at puberty.
The original nomenclature of the KiSS-1 gene and its product, kisspeptin, may have been named with a bit of whimsy, to ensure everyone knew (or might guess) where it was discovered— in Hershey, Pennsylvania
, the home of the chocolate "Hershey's Kisses".
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 AR
) 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.
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms 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 ionic bonds, hydrogen...
for GPR54
KiSS1-derived peptide receptor
The 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 suppressor
Metastasis suppressor
A metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal attributes of cancer. This attribute is responsible for about ninety percent of human cancer deaths...
gene that has the ability to suppress melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
and breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
. It recently became clear that kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone
Gonadotropin-releasing hormone
Gonadotropin-releasing hormone , also known as Luteinizing-hormone-releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. GnRH is synthesized and released from neurons within...
(GnRH) at puberty, the extent of which is an area of ongoing research.
Genomics
Kisspeptins are a family of peptides encoded by the KiSS-1 gene. This gene is located on the long arm of chromosome 1 (1q32) and has four exons of which the 5' and 3' exons are only partly translated. The gene product is a 145 amino acid precursor peptide which is cleaved to 54 amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s in length, which may be further truncated to 14, 13 or 10 amino acid carboxyl terminal fragments. These N-terminally truncated peptides are known as the kisspeptins and belong to a larger family of peptides known as RFamides which all share a common arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
-NH2 motif at their C-terminus.
A polymorphism
Polymorphism (biology)
Polymorphism 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 exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
of this mRNA
Messenger RNA
Messenger RNA 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 acids: a protein...
results in two protein isoform
Protein isoform
A 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 adenosine is absent, a downstream stop codon
Stop codon
In the genetic code, a stop codon is a nucleotide triplet within messenger RNA that signals a termination of translation. Proteins are based on polypeptides, which are unique sequences of amino acids. Most codons in messenger RNA correspond to the addition of an amino acid to a growing polypeptide...
is utilized and the encoded protein extends for an additional seven amino acid residues.
Function
In the brainBrain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
this gene is transcribed within the hippocampal dentate gyrus. It is also transcribed in the vascular endothelium.
It is transcribed within the neocortex of the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
with higher levels in foetal compared to adult tissues. Kisspeptin-54 can stimulate secretion of aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
.
It is transcribed in the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
within the islet cells and where it can stimulate release of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
.
Studies suggest a putative role in the regulation of events downstream of cell-matrix adhesion, perhaps involving cytoskeletal
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
reorganization.
Pathological importance
The proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
encoded by this gene is a metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
suppressor of melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
s and breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
s without affecting tumorigenicity. The encoded protein may function to inhibit chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic 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,...
and invasion, attenuating metastasis in malignant melanomas.
It is found in atherosclerotic plaques of the coronary arteries.
Discovery
The receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
for kisspeptin, GPR54, was first identified as an orphan GPCR in rat in 1999. Following in 2001, a natural ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
for GPR54 was discovered, which was the product of the Kiss1 gene, originally identified as a human metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
suppressor gene. Subsequent mutant studies led to the discovery that LOF mutations
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in GPR54 causes failure to progress through puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
in man, due to hypogonadotropic hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
. Thus, it was concluded that Kisspeptin-GPR54 signaling is essential to initiate gonadotropin (LH/FSH) secretion at puberty.
The original nomenclature of the KiSS-1 gene and its product, kisspeptin, may have been named with a bit of whimsy, to ensure everyone knew (or might guess) where it was discovered— in Hershey, Pennsylvania
Hershey, Pennsylvania
Hershey is a census-designated place in Derry Township, Dauphin County in the 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 municipality...
, the home of the chocolate "Hershey's Kisses".
Kisspeptin Neurons
Kisspeptin expressing neurons are located in:- Anteroventral periventricular nucleusPeriventricular nucleusThe Periventricular nucleus is a thin sheet of small neurons located in the wall of the third ventricle, a composite structure of the hypothalamus. Functions in analgesia....
(AVPV) - Periventricular nucleusPeriventricular nucleusThe Periventricular nucleus is a thin sheet of small neurons located in the wall of the third ventricle, a composite structure of the hypothalamus. Functions in analgesia....
(PVN) - Anterodorsal preoptic nucleusPreoptic nucleusPreoptic nucleus can refer to:* Ventrolateral preoptic nucleus* Anterodorsal preoptic nucleus* Preoptic area...
(ADP) - The arcuate nucleusArcuate nucleusThe 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 AR
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
) 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.- GramicidinGramicidinGramicidin 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.
- Kisspeptin induces production of LH and FSH, which are required for female's menstruation. Athletes may not undergo menstruation due to low fat levels; fat produces the hormone "Leptin", which induces production of "Kisspeptin".