Tachykinin peptides

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.

Tachykinin family
Structure of the tachykinin peptide Kassinin.[1]
Identifiers
SymbolTachykinin
PfamPF02202
InterProIPR002040
SMARTTK
PROSITEPDOC00240
SCOPe1myu / SUPFAM
OPM superfamily143
OPM protein1myu

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
Main article: Tachykinin receptor

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:

  • NK1: SP > NKA > NKB
  • NK2: NKA > NKB > SP
  • NK3: NKB > NKA > SP

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
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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.
  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.
  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.
  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.
  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.
  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.
  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.
  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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