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Gene Review

TACR3  -  tachykinin receptor 3

Homo sapiens

Synonyms: HH11, NK-3 receptor, NK-3R, NK3R, NKR, ...
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Disease relevance of TACR3

  • This study aimed to examine the direct and nerve-mediated effect of specific NK1, NK2 and NK3 receptor agonists and antagonists in colonic preparations from control subjects and patients with idiopathic chronic constipation (ICC) [1].
  • No studies have examined the expression of the two NK receptor populations in pancreatic acini during pancreatitis in rats [2].
  • Studies with talnetant and other selective NK3 receptor antagonists are, therefore, revealing an exciting and novel pathway by which pathological changes in intestinal motility and nociception can be induced, suggesting a role for NK3 receptor antagonism in irritable bowel syndrome [3].
  • Given the reported location of NK-3 receptors within the rat brainstem vagal motor and sensory nuclei, we investigated the ability of SB-222200, a brain-penetrant NK-3 receptor antagonist, to interfere with emesis evoked in ferrets by the emetogenic cytotoxic agent cisplatin [4].
  • Finally, there is preclinical evidence for hypothesising an effect of NK-3 receptor antagonists on the cardiovascular disturbance that characterises pre-eclampsia [5].

Psychiatry related information on TACR3


High impact information on TACR3

  • The murine NK receptor Ly49A inhibits NK cell activity by interacting with H-2D(d) through its C-type-lectin-like NK receptor domain [8].
  • Susceptibility to the non-peptide antagonists can be conveyed to the previously unresponsive NK3 receptor by mutational transfer of this discontinuous epitope from the NK1 receptor [9].
  • In the presence of low doses of superantigen, the proliferative response of these T cell clones was three- to ninefold greater when the T cells were costimulated by way of the NK receptor [10].
  • The gp42 binds HLA-DR1 using a surface site that is distinct from the canonical lectin and NK receptor ligand binding sites [11].
  • This unexpected intercellular transfer of HLA-C is dependent on NK receptor recognition, since HLA-Cw6 or -Cw4 but not -Cw3 transfer to an NK transfectant expressing killer Ig-like receptor (KIR)2DL1 [12].

Biological context of TACR3


Anatomical context of TACR3


Associations of TACR3 with chemical compounds

  • The rank order of tachykinin peptides competing for [3H]senktide binding at the NK-3 receptor homolog was [MePhe7]neurokinin B > senktide > substance P = neurokinin A > neurokinin B [13].
  • Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (53, SB 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK-3 receptor antagonists [22].
  • A stepwise chemical modification from human neurokinin-3 receptor (hNK-3R)-selective antagonists to potent and combined hNK-3R and hNK-2R antagonists using the same 2-phenylquinoline template is described [23].
  • However, the pharmacological profiles of [MePhe7]-NKB, SR 142801 and SR 48968 suggest the presence of an 'atypical' NK3 receptor or a heterogeneous population of NK3 receptors in this tissue [24].
  • Using a chimeric genomic-cDNA gene, the human NK-3 receptor was expressed in Xenopus laevis oocytes where it mediates membrane conductance changes in response to its agonist, neurokinin B [25].

Regulatory relationships of TACR3

  • All three spantides failed to antagonize NKB-induced calcium responses at the NK3 receptor [26].

Other interactions of TACR3

  • The selective tachykinin NK2 receptor agonist, [beta-Ala8]neurokinin A(4-10), caused concentration-dependent contractions in healthy tissues; neither NK1 receptor-selective nor NK3 receptor-selective agonists were contractile [27].
  • The presence of TAC3 and the tachykinin NK(3) receptor (TACR3) in a wide variety of peripheral tissues argue for a still unexplored role of this ligand-receptor pair in mediating visceral effects of tachykinins [17].
  • (S)-(+)-N-(1-Cyclohexylethyl)-3-[(4-morpholin-4-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide (compound 25, SB-400238: hNK-3R binding affinity, K(i) = 0.8 nM; hNK-2R binding affinity, K(i) = 0.8 nM) emerged as the best example in this approach [23].
  • When the duration of the EFS stimulus was increased, the participation of all NK receptor subtypes became more evident [28].
  • Expression of the mRNAs for specific SP receptors, neurokinin (NK)-1R, NK-2R, and NK-3R, was demonstrated with RT-PCR [29].

Analytical, diagnostic and therapeutic context of TACR3


  1. Idiopathic chronic constipation: tachykinins as cotransmitters in colonic contraction. Mitolo-Chieppa, D., Mansi, G., Nacci, C., De Salvia, M.A., Montagnani, M., Potenza, M.A., Rinaldi, R., Lerro, G., Siro-Brigiani, G., Mitolo, C.I., Rinaldi, M., Altomare, D.F., Memeo, V. Eur. J. Clin. Invest. (2001) [Pubmed]
  2. Expression of NK-1 and NK-3 tachykinin receptors in pancreatic acinar cells after acute experimental pancreatitis in rats. Broccardo, M., Linari, G., Agostini, S., Amadoro, G., Carpino, F., Ciotti, M.T., Petrella, C., Petrozza, V., Severini, C., Improta, G. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  3. Neurokinin NK1 and NK3 receptors as targets for drugs to treat gastrointestinal motility disorders and pain. Sanger, G.J. Br. J. Pharmacol. (2004) [Pubmed]
  4. Effect of a selective and potent central nervous system penetrant, neurokinin-3 receptor antagonist (SB-222200), on cisplatin-induced emesis in the ferret. King, A.G., Sanger, G.J. Neurosci. Lett. (2005) [Pubmed]
  5. Peripheral tachykinin receptors as potential therapeutic targets in visceral diseases. Lecci, A., Maggi, C.A. Expert Opin. Ther. Targets (2003) [Pubmed]
  6. Neurokinin peptides and neurokinin receptors as potential therapeutic intervention targets of basal ganglia in the prevention and treatment of Parkinson's disease. Chen, L.W., Yung, K.K., Chan, Y.S. Current drug targets. (2004) [Pubmed]
  7. Short-term rhythms in the performance of a simple motor task. Gopher, D., Lavie, P. Journal of motor behavior. (1980) [Pubmed]
  8. Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand. Tormo, J., Natarajan, K., Margulies, D.H., Mariuzza, R.A. Nature (1999) [Pubmed]
  9. Different binding epitopes on the NK1 receptor for substance P and non-peptide antagonist. Gether, U., Johansen, T.E., Snider, R.M., Lowe, J.A., Nakanishi, S., Schwartz, T.W. Nature (1993) [Pubmed]
  10. Enhancement of class II-restricted T cell responses by costimulatory NK receptors for class I MHC proteins. Mandelboim, O., Davis, D.M., Reyburn, H.T., Valés-Gómez, M., Sheu, E.G., Pazmany, L., Strominger, J.L. Science (1996) [Pubmed]
  11. Structure of the Epstein-Barr virus gp42 protein bound to the MHC class II receptor HLA-DR1. Mullen, M.M., Haan, K.M., Longnecker, R., Jardetzky, T.S. Mol. Cell (2002) [Pubmed]
  12. Intercellular transfer and supramolecular organization of human leukocyte antigen C at inhibitory natural killer cell immune synapses. Carlin, L.M., Eleme, K., McCann, F.E., Davis, D.M. J. Exp. Med. (2001) [Pubmed]
  13. 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. Krause, J.E., Staveteig, P.T., Mentzer, J.N., Schmidt, S.K., Tucker, J.B., Brodbeck, R.M., Bu, J.Y., Karpitskiy, V.V. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  14. The primary structure and gene organization of human substance P and neuromedin K receptors. Takahashi, K., Tanaka, A., Hara, M., Nakanishi, S. Eur. J. Biochem. (1992) [Pubmed]
  15. Phylogeny of tachykinin receptor localization in the vertebrate central nervous system: apparent absence of neurokinin-2 and neurokinin-3 binding sites in the human brain. Dietl, M.M., Palacios, J.M. Brain Res. (1991) [Pubmed]
  16. Structural motifs encoded by individual exons of the human neurokinin-1 receptor gene interact differentially with selective agonists and antagonists. Tian, Y., Wu, L.H., Pu, Y., Huang, C.C., Chung, F.Z. J. Neurochem. (1996) [Pubmed]
  17. mRNA expression of tachykinins and tachykinin receptors in different human tissues. Pinto, F.M., Almeida, T.A., Hernandez, M., Devillier, P., Advenier, C., Candenas, M.L. Eur. J. Pharmacol. (2004) [Pubmed]
  18. Substance P (SP) mediates production of stem cell factor and interleukin-1 in bone marrow stroma: potential autoregulatory role for these cytokines in SP receptor expression and induction. Rameshwar, P., Gascón, P. Blood (1995) [Pubmed]
  19. Nonpeptide tachykinin receptor antagonists. II. Pharmacological and pharmacokinetic profile of SB-222200, a central nervous system penetrant, potent and selective NK-3 receptor antagonist. Sarau, H.M., Griswold, D.E., Bush, B., Potts, W., Sandhu, P., Lundberg, D., Foley, J.J., Schmidt, D.B., Webb, E.F., Martin, L.D., Legos, J.J., Whitmore, R.G., Barone, F.C., Medhurst, A.D., Luttmann, M.A., Giardina, G.A., Hay, D.W. J. Pharmacol. Exp. Ther. (2000) [Pubmed]
  20. Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist. Sarau, H.M., Griswold, D.E., Potts, W., Foley, J.J., Schmidt, D.B., Webb, E.F., Martin, L.D., Brawner, M.E., Elshourbagy, N.A., Medhurst, A.D., Giardina, G.A., Hay, D.W. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  21. Coexpression of preprotachykinin A and B transcripts in the bovine corpus luteum and evidence for functional neurokinin receptor activity in luteal endothelial cells and ovarian macrophages. Brylla, E., Aust, G., Geyer, M., Uckermann, O., Löffler, S., Spanel-Borowski, K. Regul. Pept. (2005) [Pubmed]
  22. Discovery of a novel class of selective non-peptide antagonists for the human neurokinin-3 receptor. 2. Identification of (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (SB 223412). Giardina, G.A., Raveglia, L.F., Grugni, M., Sarau, H.M., Farina, C., Medhurst, A.D., Graziani, D., Schmidt, D.B., Rigolio, R., Luttmann, M., Cavagnera, S., Foley, J.J., Vecchietti, V., Hay, D.W. J. Med. Chem. (1999) [Pubmed]
  23. Stepwise modulation of neurokinin-3 and neurokinin-2 receptor affinity and selectivity in quinoline tachykinin receptor antagonists. Blaney, F.E., Raveglia, L.F., Artico, M., Cavagnera, S., Dartois, C., Farina, C., Grugni, M., Gagliardi, S., Luttmann, M.A., Martinelli, M., Nadler, G.M., Parini, C., Petrillo, P., Sarau, H.M., Scheideler, M.A., Hay, D.W., Giardina, G.A. J. Med. Chem. (2001) [Pubmed]
  24. Characterization of NK3 receptors in rabbit isolated iris sphincter muscle. Medhurst, A.D., Parsons, A.A., Roberts, J.C., Hay, D.W. Br. J. Pharmacol. (1997) [Pubmed]
  25. Molecular characterisation, expression and localisation of human neurokinin-3 receptor. Buell, G., Schulz, M.F., Arkinstall, S.J., Maury, K., Missotten, M., Adami, N., Talabot, F., Kawashima, E. FEBS Lett. (1992) [Pubmed]
  26. Comparison of antagonist activity of spantide family at human neurokinin receptors measured by aequorin luminescence-based functional calcium assay. Janecka, A., Poels, J., Fichna, J., Studzian, K., Vanden Broeck, J. Regul. Pept. (2005) [Pubmed]
  27. Differential alterations in tachykinin NK2 receptors in isolated colonic circular smooth muscle in inflammatory bowel disease and idiopathic chronic constipation. Menzies, J.R., McKee, R., Corbett, A.D. Regul. Pept. (2001) [Pubmed]
  28. The role of tachykinins in circular muscle contractility of the murine ileum: a functional investigation. De Schepper, H.U., De Winter, B.Y., Seerden, T.C., Herman, A.G., Pelckmans, P.A., De Man, J.G. Autonomic neuroscience : basic & clinical. (2006) [Pubmed]
  29. Substance P-induced cadherin expression and its signal transduction in a cloned human corneal epithelial cell line. Araki-Sasaki, K., Aizawa, S., Hiramoto, M., Nakamura, M., Iwase, O., Nakata, K., Sasaki, Y., Mano, T., Handa, H., Tano, Y. J. Cell. Physiol. (2000) [Pubmed]
  30. Chromodacryorrhea and repetitive hind paw tapping: models of peripheral and central tachykinin NK1 receptor activation in gerbils. Bristow, L.J., Young, L. Eur. J. Pharmacol. (1994) [Pubmed]
  31. Cobalt-mediated dimerization of the human natural killer cell inhibitory receptor. Fan, Q.R., Long, E.O., Wiley, D.C. J. Biol. Chem. (2000) [Pubmed]
  32. Enhanced recognition of human NK receptors after influenza virus infection. Achdout, H., Arnon, T.I., Markel, G., Gonen-Gross, T., Katz, G., Lieberman, N., Gazit, R., Joseph, A., Kedar, E., Mandelboim, O. J. Immunol. (2003) [Pubmed]
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