Tachykinin peptides

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Tachykinin family
PDB 1myu EBI.jpg
Structure of the tachykinin peptide Kassinin. [1]
Identifiers
SymbolTachykinin
Pfam PF02202
InterPro IPR002040
SMART TK
PROSITE PDOC00240
SCOP2 1myu / SCOPe / SUPFAM
OPM superfamily 143
OPM protein 1myu

Tachykinin peptides are one of the largest families of neuropeptides, found from amphibians to mammals. They were so named due to their ability to rapidly induce contraction of gut tissue. [2] 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 genes that produce tachykinins encode precursor proteins called preprotachykinins , which are chopped apart into smaller peptides by posttranslational proteolytic processing. The genes also code for multiple splice forms that are made up of different sets of peptides.

Contents

Tachykinins [3] [4] [5] 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 [6] ), neuropeptide gamma, and Substance P. [7] 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. [2]

TAC3 encodes neurokinin B. [8]

The best known tachykinin is Substance P.

Receptors

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 antagonists), through which substance P acts, have been proposed to belong to a new class of antidepressants, [9] [10] while NK2 antagonists have been proposed as anxiolytics [11] [12] and NK3 antagonists have been proposed as antipsychotics. [13] [14]

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. [15] [16] [17] The main use for which these antagonist drugs have been applied so far, however, is as antiemetics, in both human and veterinary medicine. [18] [19]

Examples of tachykinin antagonists include: [20]

Subfamilies

Related Research Articles

Substance P Chemical compound

Substance P (SP) is an undecapeptide member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:

Physalaemin Chemical compound

Physalaemin is a tachykinin peptide obtained from the Physalaemus frog, closely related to substance P. Its structure was first elucidated in 1964.

Kassinin Chemical compound

Kassinin is a peptide derived from the Kassina frog. It belongs to tachykinin family of neuropeptides. It is secreted as a defense response, and is involved in neuropeptide signalling.

Neurokinin 1 (NK1) antagonists (-pitants) are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. NK-1 antagonists boost the efficacy of 5-HT3 antagonists to prevent nausea and vomiting. The discovery of neurokinin 1 (NK1) receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.

Preprotachykinins are precursor proteins that are modified into tachykinin peptides. Via alternative splicing and post-translational modifications, preprotachykinins produce multiple peptide neurotransmitters.

Neurokinin A Chemical compound

Neurokinin A (NKA), formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflammatory and pain responses.

Neurokinin B Chemical compound

Neurokinin B (NKB) belongs in the family of tachykinin peptides. Neurokinin B is implicated in a variety of human functions and pathways such as the secretion of gonadotropin-releasing hormone. Additionally, NKB is associated with pregnancy in females and maturation in young adults. Reproductive function is highly dependent on levels of both neurokinin B and also the G-protein coupled receptor ligand kisspeptin. The first NKB studies done attempted to resolve why high levels of the peptide may be implicated in pre-eclampsia during pregnancy. NKB, kisspeptin, and dynorphin together are found in the arcuate nucleus (ARC) known as the KNDy subpopulation. This subpopulation is targeted by many steroid hormones and works to form a network that feeds back to GnRH pulse generator.

Tachykinin receptor 1

The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins. The protein is the product of the TACR1 gene.

Tachykinin receptor 2

Substance-K receptor is a protein that in humans is encoded by the TACR2 gene.

Tachykinin receptor 3

Tachykinin receptor 3, also known as TACR3, is a protein which in humans is encoded by the TACR3 gene.

Eledoisin Chemical compound

Eledoisin is an undecapeptide of mollusk origin, belonging to the tachykinin family of neuropeptides.

TAC3

Tachykinin-3 is a protein that in humans is encoded by the TAC3 gene.

TAC1

Preprotachykinin-1,, is a precursor protein that in humans is encoded by the TAC1 gene.

Osanetant

Osanetant (developmental code name SR-142,801) is a neurokinin 3 receptor antagonist which was developed by Sanofi-Synthélabo and was being researched for the treatment of schizophrenia but was discontinued. It was the first non-peptide NK3 antagonist developed in the mid-1990s, Other potential applications for osanetant is in the treatment of drug addiction, as it has been found to block the effects of cocaine in animal models.

GR-159897

GR-159897 is a potent and selective NK2 receptor antagonist drug. It has anxiolytic effects in animal models, and also inhibits bronchoconstriction of the airways, which may potentially make it useful in the treatment of asthma.

L-733,060

L-733,060 is a drug developed by Merck which acts as an orally active, non-peptide, selective antagonist for the NK1 receptor, binding with a Ki of 0.08 nM. Only one enantiomer is active which has made it the subject of several asymmetric synthesis efforts.

Ezlopitant

Ezlopitant (INN, code name CJ-11,974) is an NK1 receptor antagonist. It has antiemetic and antinociceptive effects. Pfizer was developing ezlopitant for the treatment of irritable bowel syndrome but it appears to have been discontinued.

Netupitant

Netupitant is an antiemetic drug. In the United States, the combination drug netupitant/palonosetron is approved by the Food and Drug Administration for prevention of acute and delayed chemotherapy-induced nausea and vomiting, including highly emetogenic chemotherapy such as with cisplatin. In Europe, it is approved by the European Medicines Agency (EMA) for the same indication.

Vofopitant

Vofopitant (GR205171) is a drug which acts as an NK1 receptor antagonist. It has antiemetic effects as with other NK1 antagonists, and also shows anxiolytic actions in animals. It was studied for applications such as the treatment of social phobia and post-traumatic stress disorder, but did not prove sufficiently effective to be marketed.

Neuropeptide K, is a protein encoded by the TAC1 gene. It is an elongated derivative of the N-terminus of neurokinin A as the final post-translational processing product of beta-preprotachykinin.

References

  1. ↑ Grace RC, Lynn AM, Cowsik SM (February 2001). "Lipid induced conformation of the tachykinin peptide Kassinin". J. Biomol. Struct. Dyn. 18 (4): 611–21, 623–5. doi:10.1080/07391102.2001.10506693. PMID   11245256. S2CID   42266413.
  2. 1 2 Carter MS, Krause JE (July 1990). "Structure, expression, and some regulatory mechanisms of the rat preprotachykinin gene encoding substance P, neurokinin A, neuropeptide K, and neuropeptide gamma". J. Neurosci. 10 (7): 2203–14. doi: 10.1523/JNEUROSCI.10-07-02203.1990 . PMC   6570392 . PMID   1695945.
  3. ↑ Maggio JE (1988). "Tachykinins". Annu. Rev. Neurosci. 11: 13–28. doi:10.1146/annurev.ne.11.030188.000305. PMID   3284438.
  4. ↑ Helke CJ, Krause JE, Mantyh PW, Couture R, Bannon MJ (1990). "Diversity in mammalian tachykinin peptidergic neurons: multiple peptides, receptors, and regulatory mechanisms". FASEB J. 4 (6): 1606–15. doi:10.1096/fasebj.4.6.1969374. PMID   1969374. S2CID   25935155.
  5. ↑ Avanov AIa (1992). "Tachykinins and conformational aspects of their interactions with receptors". Mol. Biol. (Mosk). 26 (1): 5–24. PMID   1324401.
  6. ↑ Dornan WA, Vink KL, Malen P, Short K, Struthers W, Barrett C (August 1993). "Site-specific effects of intracerebral injections of three neurokinins (neurokinin A, neurokinin K, and neurokinin gamma) on the expression of male rat sexual behavior". Physiol. Behav. 54 (2): 249–58. doi:10.1016/0031-9384(93)90107-Q. PMID   7690487. S2CID   33412235.
  7. ↑ Online Mendelian Inheritance in Man (OMIM): TAC1 - 162320
  8. ↑ Online Mendelian Inheritance in Man (OMIM): TAC3 - 162330
  9. ↑ Alvaro G, Di Fabio R (September 2007). "Neurokinin 1 receptor antagonists--current prospects". Curr Opin Drug Discov Dev. 10 (5): 613–21. PMID   17786860.
  10. ↑ Duffy RA (May 2004). "Potential therapeutic targets for neurokinin-1 receptor antagonists". Expert Opin Emerg Drugs. 9 (1): 9–21. doi:10.1517/eoed.9.1.9.32956. PMID   15155133.
  11. ↑ Salomé N, Stemmelin J, Cohen C, Griebel G (April 2006). "Selective blockade of NK2 or NK3 receptors produces anxiolytic- and antidepressant-like effects in gerbils". Pharmacol. Biochem. Behav. 83 (4): 533–9. doi:10.1016/j.pbb.2006.03.013. PMID   16624395. S2CID   15134994.
  12. ↑ Louis C, Stemmelin J, Boulay D, Bergis O, Cohen C, Griebel G (March 2008). "Additional evidence for anxiolytic- and antidepressant-like activities of saredutant (SR48968), an antagonist at the neurokinin-2 receptor in various rodent-models". Pharmacol. Biochem. Behav. 89 (1): 36–45. doi:10.1016/j.pbb.2007.10.020. PMID   18045668. S2CID   21490514.
  13. ↑ Spooren W, Riemer C, Meltzer H (December 2005). "Opinion: NK3 receptor antagonists: the next generation of antipsychotics?". Nat Rev Drug Discov. 4 (12): 967–75. doi:10.1038/nrd1905. PMID   16341062. S2CID   13270787.
  14. ↑ Chahl LA (August 2006). "Tachykinins and neuropsychiatric disorders". Curr Drug Targets. 7 (8): 993–1003. doi:10.2174/138945006778019309. PMID   16918327.
  15. ↑ Groneberg DA, Harrison S, Dinh QT, Geppetti P, Fischer A (August 2006). "Tachykinins in the respiratory tract". Curr Drug Targets. 7 (8): 1005–10. doi:10.2174/138945006778019318. PMID   16918328.
  16. ↑ Improta G, Broccardo M (August 2006). "Tachykinins: role in human gastrointestinal tract physiology and pathology". Curr Drug Targets. 7 (8): 1021–9. doi:10.2174/138945006778019354. PMID   16918330.
  17. ↑ Boot JD, de Haas S, Tarasevych S, et al. (March 2007). "Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma". Am. J. Respir. Crit. Care Med. 175 (5): 450–7. doi:10.1164/rccm.200608-1186OC. PMID   17170385.
  18. ↑ Navari RM (December 2007). "Fosaprepitant (MK-0517): a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting". Expert Opin Investig Drugs. 16 (12): 1977–85. doi:10.1517/13543784.16.12.1977. PMID   18042005. S2CID   21437603.
  19. ↑ Hickman MA, Cox SR, Mahabir S, et al. (June 2008). "Safety, pharmacokinetics and use of the novel NK-1 receptor antagonist maropitant (Cerenia) for the prevention of emesis and motion sickness in cats". J. Vet. Pharmacol. Ther. 31 (3): 220–9. doi:10.1111/j.1365-2885.2008.00952.x. PMID   18471143.
  20. ↑ Quartara L, Altamura M (August 2006). "Tachykinin receptors antagonists: from research to clinic". Curr Drug Targets. 7 (8): 975–92. doi:10.2174/138945006778019381. PMID   16918326.
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