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Tachykinin receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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Tachykinin receptors (provisional nomenclature as recommended by NC-IUPHAR [18]) are activated by the endogenous peptides substance P (TAC1, P20366) (SP), neurokinin A (TAC1, P20366) (NKA; previously known as substance K, neurokinin α, neuromedin L), neurokinin B (TAC3, Q9UHF0) (NKB; previously known as neurokinin β, neuromedin K), neuropeptide K (TAC1, P20366) and neuropeptide γ (TAC1, P20366) (N-terminally extended forms of neurokinin A). The neurokinins (A and B) are mammalian members of the tachykinin family, which includes peptides of mammalian and nonmammalian origin containing the consensus sequence: Phe-x-Gly-Leu-Met. Marked species differences in in vitro pharmacology exist for all three receptors, in the context of nonpeptide ligands. Antagonists such as aprepitant and fosaprepitant were approved by FDA and EMA, in combination with other antiemetic agents, for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.
Receptors
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NK1 receptor
C
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NK2 receptor
C
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NK3 receptor
C
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Further reading
* Key recommended reading is highlighted with an asterisk
Cieri-Hutcherson NE, Marji EK, Hutcherson TC. (2024) Systematic review of neurokinin-3 receptor antagonists for the management of vasomotor symptoms of menopause. Menopause, 31 (4): 342-354. [PMID:38471077]
Commons KG. (2010) Neuronal pathways linking substance P to drug addiction and stress. Brain Res, 1314: 175-82. [PMID:19913520]
* Douglas SD, Leeman SE. (2011) Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Ann N Y Acad Sci, 1217: 83-95. [PMID:21091716]
* Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]
Garcia-Recio S, Gascón P. (2015) Biological and Pharmacological Aspects of the NK1-Receptor. Biomed Res Int, 2015: 495704. [PMID:26421291]
* Jones S, Gibbins JM. (2008) The neurokinin 1 receptor: a potential new target for anti-platelet therapy?. Curr Opin Pharmacol, 8 (2): 114-9. [PMID:18296119]
Muñoz M, Coveñas R. (2016) Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: A new approach. Saudi J Gastroenterol, 22 (4): 260-8. [PMID:27488320]
Pantaleo N, Chadwick W, Park SS, Wang L, Zhou Y, Martin B, Maudsley S. (2010) The mammalian tachykinin ligand-receptor system: an emerging target for central neurological disorders. CNS Neurol Disord Drug Targets, 9 (5): 627-35. [PMID:20632965]
Rance NE, Krajewski SJ, Smith MA, Cholanian M, Dacks PA. (2010) Neurokinin B and the hypothalamic regulation of reproduction. Brain Res, 1364: 116-28. [PMID:20800582]
Rojas C, Slusher BS. (2012) Pharmacological mechanisms of 5-HT₃ and tachykinin NK₁ receptor antagonism to prevent chemotherapy-induced nausea and vomiting. Eur J Pharmacol, 684 (1-3): 1-7. [PMID:22425650]
* Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW. (2014) Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol Rev, 94 (1): 265-301. [PMID:24382888]
Tuluc F, Lai JP, Kilpatrick LE, Evans DL, Douglas SD. (2009) Neurokinin 1 receptor isoforms and the control of innate immunity. Trends Immunol, 30 (6): 271-6. [PMID:19427266]
* Yin J, Chapman K, Clark LD, Shao Z, Borek D, Xu Q, Wang J, Rosenbaum DM. (2018) Crystal structure of the human NK1 tachykinin receptor. Proc Natl Acad Sci USA, 115 (52): 13264-13269. [PMID:30538204]
References
1. Anthes JC, Chapman RW, Richard C, Eckel S, Corboz M, Hey JA, Fernandez X, Greenfeder S, McLeod R, Sehring S et al.. (2002) SCH 206272: a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist. Eur J Pharmacol, 450 (2): 191-202. [PMID:12206858]
2. Bahouth SW, Musacchio JM. (1985) Specific binding of [3H]substance P to the rat submaxillary gland. The effects of ions and guanine nucleotides. J Pharmacol Exp Ther, 234 (2): 326-36. [PMID:2410593]
3. Beaujouan JC, Saffroy M, Torrens Y, Glowinski J. (1997) Potency and selectivity of the tachykinin NK3 receptor antagonist SR 142801. Eur J Pharmacol, 319 (2-3): 307-16. [PMID:9042606]
4. Bellucci F, Carini F, Catalani C, Cucchi P, Lecci A, Meini S, Patacchini R, Quartara L, Ricci R, Tramontana M et al.. (2002) Pharmacological profile of the novel mammalian tachykinin, hemokinin 1. Br J Pharmacol, 135 (1): 266-74. [PMID:11786503]
5. Bennacef I, Tymciu S, Dhilly M, Lasne MC, Debruyne D, Perrio C, Barré L. (2004) Synthesis and biological evaluation of novel fluoro and iodo quinoline carboxamides as potential ligands of NK-3 receptors for in vivo imaging studies. Bioorg Med Chem, 12 (16): 4533-41. [PMID:15265501]
6. Beresford IJ, Sheldrick RL, Ball DI, Turpin MP, Walsh DM, Hawcock AB, Coleman RA, Hagan RM, Tyers MB. (1995) GR159897, a potent non-peptide antagonist at tachykinin NK2 receptors. Eur J Pharmacol, 272 (2-3): 241-8. [PMID:7713168]
7. Boden P, Eden JM, Hodgson J, Horwell DC, Hughes J, McKnight AT, Lewthwaite RA, Pritchard MC, Raphy J, Meecham K et al.. (1996) Use of a dipeptide chemical library in the development of non-peptide tachykinin NK3 receptor selective antagonists. J Med Chem, 39 (8): 1664-75. [PMID:8648606]
8. Bradshaw CG, Ceszkowski K, Turcatti G, Beresford IJ, Chollet A. (1994) Synthesis and characterization of selective fluorescent ligands for the neurokinin NK2 receptor. J Med Chem, 37 (13): 1991-5. [PMID:8027981]
9. Catalioto RM, Criscuoli M, Cucchi P, Giachetti A, Gianotti D, Giuliani S, Lecci A, Lippi A, Patacchini R, Quartara L et al.. (1998) MEN 11420 (Nepadutant), a novel glycosylated bicyclic peptide tachykinin NK2 receptor antagonist. Br J Pharmacol, 123 (1): 81-91. [PMID:9484857]
10. Chin FT, Morse CL, Shetty HU, Pike VW. (2006) Automated radiosynthesis of [18F]SPA-RQ for imaging human brain NK1 receptors with PET. J Label Comp Radiopharm, (49): 17-31.
11. Chung FZ, Wu LH, Tian Y, Vartanian MA, Lee H, Bikker J, Humblet C, Pritchard MC, Raphy J, Suman-Chauhan N. (1995) Two classes of structurally different antagonists display similar species preference for the human tachykinin neurokinin3 receptor. Mol Pharmacol, 48 (4): 711-6. [PMID:7476898]
12. Cialdai C, Tramontana M, Patacchini R, Lecci A, Catalani C, Catalioto RM, Meini S, Valenti C, Altamura M, Giuliani S et al.. (2006) MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist. Eur J Pharmacol, 549 (1-3): 140-8. [PMID:16979621]
13. Deal MJ, Hagan RM, Ireland SJ, Jordan CC, McElroy AB, Porter B, Ross BC, Stephens-Smith M, Ward P. (1992) Conformationally constrained tachykinin analogues: potent and highly selective neurokinin NK-2 receptor agonists. J Med Chem, 35 (22): 4195-204. [PMID:1331460]
14. Donaldson LF, Haskell CA, Hanley MR. (1996) Functional characterization by heterologous expression of a novel cloned tachykinin peptide receptor. Biochem J, 320 ( Pt 1): 1-5. [PMID:8947459]
15. Emonds-Alt X, Bichon D, Ducoux JP, Heaulme M, Miloux B, Poncelet M, Proietto V, Van Broeck D, Vilain P, Neliat G. (1995) SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor. Life Sci, 56 (1): PL27-32. [PMID:7830490]
16. Emonds-Alt X, Golliot F, Pointeau P, Le Fur G, Breliere JC. (1993) Characterization of the binding sites of [3H]SR 48968, a potent nonpeptide radioligand antagonist of the neurokinin-2 receptor. Biochem Biophys Res Commun, 191 (3): 1172-7. [PMID:7682062]
17. Fong TM, Yu H, Strader CD. (1992) Molecular basis for the species selectivity of the neurokinin-1 receptor antagonists CP-96,345 and RP67580. J Biol Chem, 267 (36): 25668-71. [PMID:1281470]
18. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]
19. Francis BE, Swain C, Sabin V, Burns HD. (1994) Radioiodinated L-703,606: a potent, selective antagonist to the human NK1 receptor. Appl Radiat Isot, 45 (1): 97-103. [PMID:8287060]
20. Giannotti D, Perrotta E, Di Bugno C, Nannicini R, Harmat NJ, Giolitti A, Patacchini R, Renzetti AR, Rotondaro L, Giuliani S et al.. (2000) Discovery of potent cyclic pseudopeptide human tachykinin NK-2 receptor antagonists. J Med Chem, 43 (22): 4041-4. [PMID:11063600]
21. Giardina GA, Sarau HM, Farina C, Medhurst AD, Grugni M, Foley JJ, Raveglia LF, Schmidt DB, Rigolio R, Vassallo M et al.. (1996) 2-Phenyl-4-quinolinecarboxamides: a novel class of potent and selective non-peptide competitive antagonists for the human neurokinin-3 receptor. J Med Chem, 39 (12): 2281-4. [PMID:8691422]
22. Grisshammer R, Little J, Aharony D. (1994) Expression of rat NK-2 (neurokinin A) receptor in E. coli. Recept Channels, 2 (4): 295-302. [PMID:7719707]
23. Guard S, Watson SP, Maggio JE, Too HP, Watling KJ. (1990) Pharmacological analysis of [3H]-senktide binding to NK3 tachykinin receptors in guinea-pig ileum longitudinal muscle-myenteric plexus and cerebral cortex membranes. Br J Pharmacol, 99 (4): 767-73. [PMID:1694464]
24. Hagan RM, Beresford IJ, Stables J, Dupere J, Stubbs CM, Elliott PJ, Sheldrick RL, Chollet A, Kawashima E, McElroy AB et al.. (1993) Characterisation, CNS distribution and function of NK2 receptors studied using potent NK2 receptor antagonists. Regul Pept, 46 (1-2): 9-19. [PMID:8210508]
25. Hale JJ, Mills SG, MacCoss M, Dorn CP, Finke PE, Budhu RJ, Reamer RA, Huskey SE, Luffer-Atlas D, Dean BJ et al.. (2000) Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. J Med Chem, 43 (6): 1234-41. [PMID:10737756]
26. Hale JJ, Mills SG, MacCoss M, Finke PE, Cascieri MA, Sadowski S, Ber E, Chicchi GG, Kurtz M, Metzger J et al.. (1998) Structural optimization affording 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J Med Chem, 41 (23): 4607-14. [PMID:9804700]
27. Harrison T, Owens AP, Williams BJ, Swain CJ, Williams A, Carlson EJ, Rycroft W, Tattersall FD, Cascieri MA, Chicchi GG et al.. (2001) An orally active, water-soluble neurokinin-1 receptor antagonist suitable for both intravenous and oral clinical administration. J Med Chem, 44 (24): 4296-9. [PMID:11708932]
28. Hastrup H, Schwartz TW. (1996) Septide and neurokinin A are high-affinity ligands on the NK-1 receptor: evidence from homologous versus heterologous binding analysis. FEBS Lett, 399: 264-266. [PMID:8985159]
29. Kamali F. (2001) Osanetant Sanofi-Synthélabo. Curr Opin Investig Drugs, 2 (7): 950-6. [PMID:11757797]
30. Krause JE, Staveteig PT, Mentzer JN, Schmidt SK, Tucker JB, Brodbeck RM, Bu JY, Karpitskiy VV. (1997) Functional expression of a novel human neurokinin-3 receptor homolog that binds [3H]senktide and [125I-MePhe7]neurokinin B, and is responsive to tachykinin peptide agonists. Proc Natl Acad Sci USA, 94 (1): 310-5. [PMID:8990205]
31. Matuszek MA, Zeng XP, Strigas J, Burcher E. (1998) An investigation of tachykinin NK2 receptor subtypes in the rat. Eur J Pharmacol, 352 (1): 103-9. [PMID:9718274]
32. Muñoz M, Coveñas R. (2020) Neurokinin receptor antagonism: a patent review (2014-present). Expert Opin Ther Pat, 30 (7): 527-539. [PMID:32401556]
33. Oury-Donat F, Carayon P, Thurneyssen O, Pailhon V, Emonds-Alt X, Soubrié P, Le Fur G. (1995) Functional characterization of the nonpeptide neurokinin3 (NK3) receptor antagonist, SR142801 on the human NK3 receptor expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther, 274 (1): 148-54. [PMID:7616392]
34. Roush ED, Kwatra MM. (1998) Human substance P receptor expressed in Chinese hamster ovary cells directly activates G(alpha q/11), G(alpha s), G(alpha o). FEBS Lett, 428 (3): 291-4. [PMID:9654151]
35. Sarau HM, Feild JA, Ames RS, Foley JJ, Nuthulaganti P, Schmidt DB, Buckley PT, Elshourbagy NA, Brawner ME, Luttmann MA et al.. (2001) Molecular and pharmacological characterization of the murine tachykinin NK(3) receptor. Eur J Pharmacol, 413 (2-3): 143-50. [PMID:11226387]
36. Sarau HM, Griswold DE, Potts W, Foley JJ, Schmidt DB, Webb EF, Martin LD, Brawner ME, Elshourbagy NA, Medhurst AD et al.. (1997) Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist. J Pharmacol Exp Ther, 281 (3): 1303-11. [PMID:9190866]
37. Schöppe J, Ehrenmann J, Klenk C, Rucktooa P, Schütz M, Doré AS, Plückthun A. (2019) Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists. Nat Commun, 10 (1): 17. [PMID:30604743]
38. Smith PW, Cooper AW, Bell R, Beresford IJ, Gore PM, McElroy AB, Pritchard JM, Saez V, Taylor NR, Sheldrick RL. (1995) New spiropiperidines as potent and selective non-peptide tachykinin NK2 receptor antagonists. J Med Chem, 38 (19): 3772-9. [PMID:7562907]
39. Spitsin S, Tebas P, Barrett JS, Pappa V, Kim D, Taylor D, Evans DL, Douglas SD. (2017) Antiinflammatory effects of aprepitant coadministration with cART regimen containing ritonavir in HIV-infected adults. JCI Insight, 2 (19). [PMID:28978797]
40. Takeda Y, Chou KB, Takeda J, Sachais BS, Krause JE. (1991) Molecular cloning, structural characterization and functional expression of the human substance P receptor. Biochem Biophys Res Commun, 179 (3): 1232-40. [PMID:1718267]
41. Tian Y, Wu LH, Oxender DL, Chung FZ. (1996) The unpredicted high affinities of a large number of naturally occurring tachykinins for chimeric NK1/NK3 receptors suggest a role for an inhibitory domain in determining receptor specificity. J Biol Chem, 271 (34): 20250-7. [PMID:8702757]
42. Torrens Y, Saffroy M, Glowinski J, Beaujouan JC. (1997) Substance P(6-11) and natural tachykinins interact with septide-sensitive tachykinin receptors coupled to a phospholipase C in the rat urinary bladder. Neuropeptides, 31 (3): 243-51. [PMID:9243521]
43. Tousignant C, Guillemette G, Drapeau G, Télémaque S, Dion S, Regoli D. (1990) 125I-BH[Sar9, Met(O2)11]-SP, a new selective ligand for the NK-1 receptor in the central nervous system. Brain Res, 524 (2): 263-70. [PMID:1705465]
44. Warner FJ, Comis A, Miller RC, Burcher E. (1999) Characterization of the [125I]-neurokinin A binding site in the circular muscle of human colon. Br J Pharmacol, 127 (5): 1105-10. [PMID:10455255]
45. Yin J, Chapman K, Clark LD, Shao Z, Borek D, Xu Q, Wang J, Rosenbaum DM. (2018) Crystal structure of the human NK1 tachykinin receptor. Proc Natl Acad Sci USA, 115 (52): 13264-13269. [PMID:30538204]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Steven D. Douglas (Chairperson)
Susan E. Leeman (Chairperson)
Christa Y. Heyward |
Other contributors:
Jeffrey Barrett
Brenden Canning
Joseph Coulson
Erin Dombrowsky
Tung M. Fong
Pranela Remeshwar |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
The NK1 receptor has also been described to couple to G proteins other than Gq/11 [34]. The crystal structure of the human NK1 receptor in complex with antagonists has been determined [37,45]. The hexapeptide agonist septide appears to bind to an overlapping but non-identical site to substance P (TAC1, P20366) on the NK1 receptor. There are additional subtypes of tachykinin receptor; an orphan receptor (SwissProt P30098) with structural similarities to the NK3 receptor was found to respond to NKB when expressed in Xenopus oocytes or Chinese hamster ovary cells [14,30]. NK1 receptor antagonists affect cellular physiology including inflammation, apoptosis and cell trafficking and have a role in therapeutics [32,39].