Tachykinin peptides
Encyclopedia
Tachykinin peptides are one of the largest family of neuropeptide
s, found from amphibian
s to mammal
s. They were so named due to their ability to rapidly induce contraction of gut tissue. The tachykinin family is characterized by a common C-terminal sequence, Phe
-X-Gly
-Leu
-Met
-NH2, where X is either an Aromatic
or an Aliphatic amino acid
. The gene
s that produce tachykinins encode precursor proteins called preprotachykinins, which are chopped apart into smaller peptide
s by posttranslational proteolytic processing. The genes also code for multiple splice forms that are made up of different sets of peptides.
Tachykinins excite neurons, evoke behavioral responses, are potent vasodilators and contract (directly or indirectly) many smooth muscles. Tachykinins are from ten to twelve residues long.
The two human tachykinin genes are called TAC1
and TAC3
for historical reasons, and are equivalent to Tac1 and Tac2 of the mouse, respectively.
TAC1 encodes neurokinin A
(formerly known as substance K), neuropeptide K (which has also been called neurokinin K), neuropeptide gamma, and substance P
. Alpha, beta, and gamma splice forms are produced; the alpha form lacks exon
6 and the gamma form lacks exon 4. All three splice forms of TAC1 produce substance P, but only the beta and gamma forms produce the other three peptides. Neuropeptide K and neuropeptide gamma are N-terminally longer versions of neurokinin A that appear to be final peptide products in some tissues.
TAC3 encodes neurokinin B
.
The most notable tachykinin is Substance P
.
There are three known mammalian tachykinin receptors termed NK1, NK2 and NK3. All are members of the 7 transmembrane g protein-coupled family of receptors and induce the activation of phospholipase C
, producing inositol triphosphate
. NK1, NK2 and NK3 selectively bind to substance P
, neurokinin A
, and neurokinin B
, respectively. Whilst the receptors are not specific to any individual tachykinin, they do have differing affinity for the tachykinins:
Antagonists of neurokinin-1 (NK1) receptors (NK1 receptor antagonist
s), through which substance P acts, have been proposed to belong to a new class of antidepressant
s,
while NK2 antagonists have been proposed as anxiolytics and NK3 antagonists have been proposed as antipsychotics.
Tachykinin peptides are also involved in inflammation
, and tachykinin receptor antagonists have been researched for use in treating inflammatory conditions such as asthma
and irritable bowel syndrome
.
The main use for which these drugs have been applied so far, however, is as antiemetic
s, in both human and veterinary medicine.
Examples of tachykinin antagonists include:
Neuropeptide
Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
s, found from amphibian
Amphibian
Amphibians , are a class of vertebrate animals including animals such as toads, frogs, caecilians, and salamanders. They are characterized as non-amniote ectothermic tetrapods...
s to mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s. They were so named due to their ability to rapidly induce contraction of gut tissue. The tachykinin family is characterized by a common C-terminal sequence, Phe
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...
-X-Gly
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
-Leu
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
-Met
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
-NH2, where X is either an Aromatic
Aromaticity
In organic chemistry, Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. The earliest use of the term was in an article by August...
or an Aliphatic amino acid
Amino 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...
. The gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s that produce tachykinins encode precursor proteins called preprotachykinins, which are chopped apart into smaller peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s by posttranslational proteolytic processing. The genes also code for multiple splice forms that are made up of different sets of peptides.
Tachykinins excite neurons, evoke behavioral responses, are potent vasodilators and contract (directly or indirectly) many smooth muscles. Tachykinins are from ten to twelve residues long.
The two human tachykinin genes are called TAC1
TAC1
Protachykinin-1 is a protein that in humans is encoded by the TAC1 gene.-Further reading:...
and TAC3
TAC3
Tachykinin-3 is a protein that in humans is encoded by the TAC3 gene.-Further reading:...
for historical reasons, and are equivalent to Tac1 and Tac2 of the mouse, respectively.
TAC1 encodes neurokinin A
Neurokinin A
Neurokinin A is a member of the tachykinin family of neuropeptide neurotransmitters. It is produced from the same preprotachykinin A gene as the neuropeptide substance P. It has various roles in the body of humans and other animals...
(formerly known as substance K), neuropeptide K (which has also been called neurokinin K), neuropeptide gamma, and substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
. Alpha, beta, and gamma splice forms are produced; the alpha form lacks 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...
6 and the gamma form lacks exon 4. All three splice forms of TAC1 produce substance P, but only the beta and gamma forms produce the other three peptides. Neuropeptide K and neuropeptide gamma are N-terminally longer versions of neurokinin A that appear to be final peptide products in some tissues.
TAC3 encodes neurokinin B
Neurokinin B
Neurokinin B is a tachykinin peptide.It is found in higher concentration in pregnant women suffering pre-eclampsia and can bind the immune-cloaking molecule phosphocholine....
.
The most notable tachykinin is Substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
.
Receptors
- See main article at tachykinin receptorTachykinin receptorThere are three known mammalian tachykinin receptors termed NK1, NK2 and NK3. All are members of the 7 transmembrane G-protein coupled receptor family and induce the activation of phospholipase C, producing inositol triphosphate ....
There are three known mammalian tachykinin receptors termed NK1, NK2 and NK3. All are members of the 7 transmembrane g protein-coupled family of receptors and induce the activation of phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
, producing inositol triphosphate
Inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol , is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell...
. NK1, NK2 and NK3 selectively bind to substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
, neurokinin A
Neurokinin A
Neurokinin A is a member of the tachykinin family of neuropeptide neurotransmitters. It is produced from the same preprotachykinin A gene as the neuropeptide substance P. It has various roles in the body of humans and other animals...
, and neurokinin B
Neurokinin B
Neurokinin B is a tachykinin peptide.It is found in higher concentration in pregnant women suffering pre-eclampsia and can bind the immune-cloaking molecule phosphocholine....
, respectively. Whilst the receptors are not specific to any individual tachykinin, they do have differing affinity for the tachykinins:
- NK1: SP>NKA>NKB
- NK2: NKA>NKB>SP
- NK3: NKB>NKA>SP.
Antagonists of neurokinin-1 (NK1) receptors (NK1 receptor antagonist
NK1 receptor antagonist
Neurokinin 1 antagonists are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. The discovery of neurokinin 1 receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.An example of...
s), through which substance P acts, have been proposed to belong to a new class of antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s,
while NK2 antagonists have been proposed as anxiolytics and NK3 antagonists have been proposed as antipsychotics.
Tachykinin peptides are also involved in inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, and tachykinin receptor antagonists have been researched for use in treating inflammatory conditions such as asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
and irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
.
The main use for which these drugs have been applied so far, however, is as antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
s, in both human and veterinary medicine.
Examples of tachykinin antagonists include:
- AprepitantAprepitantAprepitant is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists . It mediates its effect by blocking the neurokinin 1 receptor.Aprepitant is manufactured by Merck & Co...
- CasopitantCasopitantCasopitant is an neurokinin 1 receptor antagonist undergoing research for the treatment of chemotherapy-induced nausea and vomiting . It is currently under development by GlaxoSmithKline ....
- FosaprepitantFosaprepitantFosaprepitant is an antiemetic drug, administered intravenously. It is a prodrug of aprepitant....
- MaropitantMaropitantMaropitant , used as maropitant citrate , is a neurokinin receptor antagonist, which was developed by Pfizer Animal Health specifically for the treatment of motion sickness and vomiting in dogs. It has not been approved by the FDA for use in any animal except dogs...
- Nepadutant
- OsanetantOsanetantOsanetant is a neurokinin 3 receptor antagonist developed by Sanofi-Synthélabo, which is being researched for the treatment of schizophrenia. It was the first non-peptide NK3 antagonist developed in the mid-1990s, and has still not made it to market, although clinical trials are continuing...
- SaredutantSaredutantSaredutant is a drug that acts as a NK2 receptor antagonist. It was under development by Sanofi-Aventis as a novel antidepressant and anxiolytic and made it to phase III clinical trials...
- TalnetantTalnetantTalnetant is a neurokinin 3 receptor antagonist developed by GlaxoSmithKline, which is being researched for several different functions, primarily for irritable bowel syndrome and as a potential antipsychotic drug for the treatment of schizophrenia....