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Tachykinin peptides are one of the largest family of neuropeptides, found from amphibians to mammals. They were so named due to their ability to rapidly induce contraction of gut tissue.[1] 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 which are made up of different sets of peptides.

Tachykinins[2][3][4] excite neurons, evoke behavioral responses, are potent vasodilatators 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[5]), neuropeptide gamma, and substance P.[6] 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 which appear to be final peptide products in some tissues.[1]

TAC3 encodes neurokinin B.[7]

The most notable tachykinin is Substance P.

Receptors Edit

See main article at 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,[8] [9] while NK2 antagonists have been proposed as anxiolytics[10][11] and NK3 antagonists have been proposed as antipsychotics.[12] [13]

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.[14] [15] [16] The main use for which these drugs have been applied so far, however, is as antiemetics, in both human and veterinary medicine.[17] [18]

Examples of tachykinin antagonists include:[19]

SubfamiliesEdit


ReferencesEdit

  1. 1.0 1.1 PMID 1695945
  2. Maggio JE (1988). Tachykinins. Annu. Rev. Neurosci. 11: 13-28.
  3. 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): 1606-1615.
  4. Avanov AIa (1992). Tachykinins and conformational aspects of their interactions with receptors. Mol. Biol. (Mosk) 26 (1): 5-24.
  5. PMID 7690487
  6. OMIM:TAC1.
  7. OMIM:TAC3.
  8. Alvaro G, Di Fabio R (September 2007). Neurokinin 1 receptor antagonists--current prospects. Curr Opin Drug Discov Devel 10 (5): 613–21.
  9. Duffy RA (May 2004). Potential therapeutic targets for neurokinin-1 receptor antagonists. Expert Opin Emerg Drugs 9 (1): 9–21.
  10. 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.
  11. 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.
  12. 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.
  13. Chahl LA (August 2006). Tachykinins and neuropsychiatric disorders. Curr Drug Targets 7 (8): 993–1003.
  14. Groneberg DA, Harrison S, Dinh QT, Geppetti P, Fischer A (August 2006). Tachykinins in the respiratory tract. Curr Drug Targets 7 (8): 1005–10.
  15. Improta G, Broccardo M (August 2006). Tachykinins: role in human gastrointestinal tract physiology and pathology. Curr Drug Targets 7 (8): 1021–9.
  16. 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.
  17. 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.
  18. 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.
  19. Quartara L, Altamura M (August 2006). Tachykinin receptors antagonists: from research to clinic. Curr Drug Targets 7 (8): 975–92.

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