Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Neurokinin-1 Receptor

  • Miguel MuñozEmail author
  • Marisa Rosso
  • Rafael Coveñas
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101781


Historical Background

The undecapeptide substance P (SP) belongs to the tachykinin peptide family (hemokinin 1 (HK-1), neurokinin A (NKA), and B (NKB) are also included in this family). This family of peptides exerts many biological actions through three receptors named neurokinin-1, neurokinin-2, and neurokinin-3. The neurokinin-1 receptor (NK-1R) shows a preferential affinity for SP/HK-1, NK-2R for NKA, and NK-3R for NKB (Pennefather et al. 2004). The affinity of the NK-1R for NKA and NKB is, respectively, 100- and 500-fold lower than for SP (Gerard et al. 1991). SP, after binding to the NK-1R, exerts many biological actions (Muñoz and Coveñas 2014). The NK-1R protein is encoded by the TACR1 gene (Takeda et al. 1991). In humans, this gene is located on chromosome 2 and spans 45–60 kb, and it is contained in five exons (Gerard et al. 1991). The NK-1R belongs to the 1 (rhodopsin-like) G...

This is a preview of subscription content, log in to check access.



The authors wish to thank Mr. Javier Muñoz (University of Seville, Spain) for technical assistance.


  1. Akazawa T, Kwatra SG, Goldsmith LE, Richardson MD, Cox EA, Sampson JH, Kwatra MM. A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas. J Neurochem. 2009;109:1079–86.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Barrett JS, Spitsin S, Moorthy G, Barrett K, Baker K, Lackner A, Tulic F, Winters A, Evans DL, Douglas SD. Pharmacologic rationale for the NK1R antagonist, aprepitant as adjunctive therapy in HIV. J Transl Med. 2016;14:148.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Berger M, Neth O, Ilmer M, Garnier A, Salinas-Martín MV, de Agustín Asencio JC, von Schweinitz D, Kappler R, Muñoz M. Hepatoblastoma cells express truncated neurokinin-1 receptor and can be inhibited by aprepitant in vitro and in vivo. J Hepatol. 2014;60:985–94.CrossRefPubMedGoogle Scholar
  4. DeFea KA, Vaughn ZD, O’Bryan EM, Nishijima D, Déry O, Bunnett NW. The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta-arrestin-dependent scaffolding complex. Proc Natl Acad Sci U S A. 2000;97:11086–91.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Douglas SD, Leeman SE. Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Ann N Y Acad Sci. 2010;1217:83–95.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Esteban F, Muñoz M, González-Moles MA, Rosso M. A role for substance P in cancer promotion and progression: a mechanism to counteract intracellular death signals following oncogene activation or DNA damage. Cancer Metastasis Rev. 2006;25:137–45.CrossRefPubMedGoogle Scholar
  7. Fong TM, Anderson SA, Yu H, Huang RR, Strader CD. Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor. Mol Pharmacol. 1992;41:24–30.PubMedGoogle Scholar
  8. Garcia M, Sakamoto K, Shigekawa M, Nakanishi S, Ito S. Multiple mechanisms of arachidonic acid release in Chinese hamster ovary cells transfected with cDNA of substance P receptor. Biochem Pharmacol. 1994;48:1735–41.CrossRefPubMedGoogle Scholar
  9. García-Recio S, Gascón P. Biological and pharmacological aspects of the NK1-receptor. Biomed Res Int. 2015;2015:495704.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Gerard NP, Garraway LA, Eddy Jr RL, Shows TB, Iijima H, Paquet JL, Gerard C. Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones. Biochemistry. 1991;30:10640–6.CrossRefPubMedGoogle Scholar
  11. Gillespie E, Leeman SE, Watts LA, Coukos JA, O’Brien MJ, Cerda SR, Farraye FA, Stucchi AF, Becker JM. Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer. Proc Natl Acad Sci U S A. 2011;108:17420–5.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Hesketh PJ, Gralla RJ, Webb RT, Ueno W, DelPrete S, Bachinsky ME, Dirlam NL, Stack CB, Silberman SL. Randomized phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis. J Clin Oncol. 1999;17:338–43.CrossRefPubMedGoogle Scholar
  13. Ho WZ, Kaufman D, Uvaydova M, Douglas SD. Substance P augments interleukin-10 and tumor necrosis factor-alpha release by human cord blood monocytes and macrophages. J Neuroimmunol. 1996;71:73–80.CrossRefPubMedGoogle Scholar
  14. Hopkins B, Powell SJ, Danks P, Briggs I, Graham A. Isolation and characterisation of the human lung NK-1 receptor cDNA. Biochem Biophys Res Commun. 1991;180:1110–7.CrossRefPubMedGoogle Scholar
  15. Kage R, Leeman SE, Krause JE, Costello CE, Boyd ND. Identification of methionine as the site of covalent attachment of a p-benzoyl-phenylalanine-containing analogue of substance P on the substance P (NK-1) receptor. J Biol Chem. 1996;271:25797–800.CrossRefPubMedGoogle Scholar
  16. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NM. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998;281:1640–5.CrossRefPubMedGoogle Scholar
  17. Lang K, Drell TL, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker KS, Entschladen F. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer. 2004;112:231–8.CrossRefPubMedGoogle Scholar
  18. Laniyonu A, Sliwinski-Lis E, Fleming N. Different tachykinin receptor subtypes are coupled to the phosphoinositide or cyclic AMP signal transduction pathways in rat submandibular cells. FEBS Lett. 1988;240:186–90.CrossRefPubMedGoogle Scholar
  19. Lee M, Choi S, Halldén G, Yo SJ, Schichnes D, Aponte GW. P2Y5 is a Gαi, Gα12/13 G protein-coupled receptor activated by lysophosphatidic acid that reduces intestinal cell adhesión. Am J Physiol Gastrointest Liver Physiol. 2009;297:G641–54.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Lieb K, Fiebich BL, Berger M, Bauer J, Schulze-Osthoff K. The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells. J Immunol. 1997;159:4952–8.PubMedGoogle Scholar
  21. Lotz M, Vaughan JH, Carson DA. Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science. 1988;241:1218–21.CrossRefPubMedGoogle Scholar
  22. Luo W, Sharif TR, Sharif M. Substance P-induced mitogenesis in human astrocytoma cells correlates with activation of the mitogen-activated protein kinase signaling pathway. Cancer Res. 1996;56:4983–91.PubMedGoogle Scholar
  23. Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin F, Kawakatsu H, Owada K, Luttrell DK, Caron MG, Lefkowitz RJ. Beta-arrestin- dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science. 1999;283:655–61.CrossRefPubMedGoogle Scholar
  24. Malbon CC. G proteins in development. Nat Rev Mol Cell Biol. 2005;6:689–701.CrossRefPubMedGoogle Scholar
  25. Medrano S, Gruenstein E, Dimlich RV. Substance P receptors on human astrocytoma cells are linked to glycogen breakdown. Neurosci Lett. 1994;167:14–8.CrossRefPubMedGoogle Scholar
  26. Meshki J, Douglas SD, Lai JP, Schwartz L, Kilpatrick LE, Tuluc F. Neurokinin 1 receptor mediates membrane blebbing in HEK293 cells through a Rho/Rho- associated coiled-coil kinase-dependent mechanism. J Biol Chem. 2009;284:9280–9.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Meshki J, Douglas SD, Hu M, Leeman SE, Tuluc F. Substance P induces rapid and transient membrane blebbing in U373MG cells in a p21-activated kinase-dependent manner. PLoS One. 2011;6:e25332.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Muñoz M, Coveñas R. Involvement of substance P and the NK-1 receptor in cancer progression. Peptides. 2013;48:1–9.CrossRefPubMedGoogle Scholar
  29. Muñoz M, Coveñas R. Involvement of substance P and NK-1 receptor in human pathology. Amino Acids. 2014;46:1727–50.CrossRefPubMedGoogle Scholar
  30. Muñoz M, Pavón A, Rosso M, Pérez A, Salinas-Martín MV, Carranza A, González A. Immunolocalization of NK-1 receptor and substance P in human normal placenta. Placenta. 2010;31:649–51.CrossRefPubMedGoogle Scholar
  31. Nakajima Y, Tsuchida K, Negishi M, Ito S, Nakanishi S. Direct linkage of three tachykinin receptors to stimulation of both phosphatidylinositol hydrolysis and cyclic AMP cascades in transfected Chinese hamster ovary cells. J Biol Chem. 1992;267:2437–42.PubMedGoogle Scholar
  32. Neer EJ. G proteins: critical control points for transmembrane signals. Protein Sci. 1994;3:3–14.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Nishimura K, Frederick J, Kwatra MM. Human substance P receptor expressed in Sf9 cells couples with multiple endogenous G proteins. J Recept Signal Transduct Res. 1998;18:51–65.CrossRefPubMedGoogle Scholar
  34. O’Connor TM, O’Connell J, O’Brien DI, Goode T, Bredin CP, Shanahan F. The role of substance P in inflammatory disease. J Cell Physiol. 2004;201:167–80.CrossRefPubMedGoogle Scholar
  35. Pennefather JN, Lecci A, Candenas ML, Patak E, Pinto FM, Maggi CA. Tachykinins and tachykinin receptors: a growing family. Life Sci. 2004;74:1445–63.CrossRefPubMedGoogle Scholar
  36. Robinson P, Garza A, Moore J, Eckols TK, Parti S, Balaji V, Vallejo J, Tweardy DJ. Substance P is required for the pathogenesis of EMCV infection in mice. Int J Clin Exp Med. 2009;2:76–86.PubMedPubMedCentralGoogle Scholar
  37. Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA. Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One. 2010;5:e10968.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Takeda Y, Chou KB, Takeda J, Sachais BS, Krause JE. Molecular cloning, structural characterization and functional expression of the human substance P receptor. Biochem Biophys Res Commun. 1991;179:1232–40.CrossRefPubMedGoogle Scholar
  39. Theoharides TC, Zhang B, Kempuraj D, Tagen M, Vasiadi M, Angelidou A, Alysandratos KD, Kalogeromitros D, Asadi S, Stavrianeas N, Peterson E, Leeman S, Conti P. IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci U S A. 2010;107:4448–53.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Wang X, Douglas SD, Lai JP, Tuluc F, Tebas P, Ho WZ. Neurokinin-1 receptor antagonist (aprepitant) inhibits drug-resistant HIV-1 infection of macrophages in vitro. J NeuroImmune Pharmacol. 2007;2:42–8.CrossRefPubMedGoogle Scholar
  41. Ziche M, Morbidelli L, Pacini M, Gepetti P, Alessandri G, Maggi CA. Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res. 1990;40:264–78.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Research Laboratory on Neuropeptides (IBIS)Virgen del Rocío University HospitalSevilleSpain
  2. 2.Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla y León (INCYL)University of SalamancaSalamancaSpain
  3. 3.Unidad de Cuidados Intensivos PediátricosVirgen del Rocío University HospitalSevilleSpain