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Gene Review

TACR2  -  tachykinin receptor 2

Homo sapiens

Synonyms: NK-2 receptor, NK-2R, NK2R, NKNAR, Neurokinin A receptor, ...
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Disease relevance of TACR2


Psychiatry related information on TACR2

  • In the same preparation MEN 11420 (0.1 microM) blocked (apparent pK(B) = 8.2) the potentiation of spontaneous motor activity produced by the NK2 receptor-selective agonist [betaAla8]NKA(4-10) [6].

High impact information on TACR2


Biological context of TACR2


Anatomical context of TACR2

  • Its release within the bone marrow (BM) can mediate bidirectional neurohematopoietic communication via specific receptors: neurokinin-1R (NK-1R), NK-2R, or NK-3R [17].
  • [3H]NKA bound in a protein-dependent, saturable (Bmax = 820 +/- 167 fmol/mg of protein), and highly specific (88 +/- 5%) manner to hNK-2R, but not to membranes from cells infected with wild-type virus (14 +/- 8%, 7 +/- 10 fmol/mg of protein) [2].
  • The data from ligand binding assays in cloned receptors combined with functional receptor assays in airway smooth muscles, demonstrate that the nonpeptide antagonist ZM253,270 is selective for the NK2 receptor species that are prevalent in hamster, compared with those found in human tissues [18].
  • These data 1) show for the first time that hHK-1 is a uterine stimulant in the human, 2) confirm that the NK2 receptor is predominant in mediating tachykinin actions on the human myometrium, and 3) indicate that mammalian tachykinin effects are tightly regulated during pregnancy in a manner that would negate an inappropriate uterotonic effect [19].
  • Tachykinin NK1 and NK2 receptor selective antagonists and agonists were used to study excitatory non-adrenergic non-cholinergic (NANC) transmission in circular muscle strips from human ileum by the sucrose-gap method [14].

Associations of TACR2 with chemical compounds

  • Site-directed mutagenesis was used to alter these residues in order to ascertain their importance in binding neurokinin A (NKA), the physiological peptide ligand for the NK2 receptor, and the non-peptide NK2 receptor selective antagonist SR48968 [12].
  • The effects of NKA and eledoisin were blocked by the NK2 receptor antagonist SR 48968 but not by the NK1 receptor antagonist SR 140333 in tissues from both groups of women [19].
  • The NK2 receptor selective agonist, [beta Ala8]NKA(4-10) (10 nM), produced a maximum enhancement of 278 +/- 83.5% (P < 0.01) (pD2 = 8.7 +/- 0.1) an effect which was blocked by MEN 10,376 (100 nM) (P < 0.05) and not by CP 96,345 [20].
  • These inhibitory effects were reversed in the presence of the CB(1) receptor-selective antagonist N-(piperidine-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (10(-7) M).ACEA did not alter LM or CM contractile responses to acetylcholine or NK-2 receptor-evoked contraction [21].
  • The effect of SP was antagonised by two selective antagonists of NK1 receptors, namely (+/-) CP 96,345 (10(-10)-10(-8) M) and FK 888 (10(-9)-10(-7) M), while the NK2 receptor antagonist MEN 10627 (10(-8)-10(-7) M) was not effective [22].

Physical interactions of TACR2

  • These results suggest that some regions of the binding site for NKA in the NK2 receptor are not used for binding SP in the NK1 receptor [12].
  • The NK-2 receptor-selective compound SR 48,968 was found to bind with low affinity to the human NK-1 receptor but with 15-fold even lower affinity to the rat receptor [23].
  • Analogues of [Leu10]NKA4-10 were synthesized in which each of the amide bonds was sequentially replaced with the reduced amide psi (CH2NH) bond to determine the effect of this structural modification on the antagonism of NKA binding to the HUB NK2 receptor [24].

Regulatory relationships of TACR2


Other interactions of TACR2

  • Using the novel ligand [4,5-3H-Leu9]neurokinin A ([4,5-3H-Leu9] NKA) in a receptor binding assay, we characterized the pharmacology of a cloned neurokinin NK-2 receptor from human lung (hNK-2R), expressed in baculovirus-infected Sf-21 insect cells [2].
  • In situ hybridization indicated NK1-receptor mRNA was expressed in submucosal glands and airway epithelial cells, whereas NK2-receptor and NK3-receptor mRNA were not detected [3].
  • We have characterized the action of the novel, water-soluble, tachykinin NK2 receptor antagonist MEN 11420 ([Asn(2-AcNH-beta-D-Glc)-Asp-Trp-Phe-Dap-Leu] c(2 beta-5 beta)) on the circular muscle of the guinea-pig and human colon in vitro and on the guinea-pig colon in vivo [30].
  • Sequence analysis of exons 1 and 5, where major differences occur between the human and animal species, provided information for polymerase chain reaction primers which allowed us to prepare full-length cDNA for the human NK-2 receptor [16].
  • Secondly, NK-2 receptor-linked AA mobilization requires concomitant PKC activation and based upon limited subtype immunodetectability as well as toxin, identical pretreatment inhibits AA release partially and blocks PKC alpha translocation completely [31].

Analytical, diagnostic and therapeutic context of TACR2


  1. Isolation and pharmacological characterization of a hamster urinary bladder neurokinin A receptor cDNA. Aharony, D., Little, J., Thomas, C., Powell, S., Berry, D., Graham, A. Mol. Pharmacol. (1994) [Pubmed]
  2. Pharmacological characterization of cloned human NK-2 (neurokinin A) receptor expressed in a baculovirus/Sf-21 insect cell system. Aharony, D., Little, J., Powell, S., Hopkins, B., Bundell, K.R., McPheat, W.L., Gordon, R.D., Hassall, G., Hockney, R., Griffin, R. Mol. Pharmacol. (1993) [Pubmed]
  3. Substance P (NK1)- and neurokinin A (NK2)-receptor gene expression in inflammatory airway diseases. Bai, T.R., Zhou, D., Weir, T., Walker, B., Hegele, R., Hayashi, S., McKay, K., Bondy, G.P., Fong, T. Am. J. Physiol. (1995) [Pubmed]
  4. Substance P (neurokinin-1) and neurokinin A (neurokinin-2) receptor gene and protein expression in the healthy and inflamed human intestine. Renzi, D., Pellegrini, B., Tonelli, F., Surrenti, C., Calabrò, A. Am. J. Pathol. (2000) [Pubmed]
  5. The NK-2 receptor antagonist SR 48968C does not improve adenosine hyperresponsiveness and airway obstruction in allergic asthma. Kraan, J., Vink-Klooster, H., Postma, D.S. Clin. Exp. Allergy (2001) [Pubmed]
  6. Excitatory motor and electrical effects produced by tachykinins in the human and guinea-pig isolated ureter and guinea-pig renal pelvis. Patacchini, R., Santicioli, P., Zagorodnyuk, V., Lazzeri, M., Turini, D., Maggi, C.A. Br. J. Pharmacol. (1998) [Pubmed]
  7. Implication of NK1 and NK2 receptors in rat colonic hypersecretion induced by interleukin 1 beta: role of nitric oxide. Eutamene, H., Theodorou, V., Fioramonti, J., Bueno, L. Gastroenterology (1995) [Pubmed]
  8. Tachykinin antagonists inhibit nerve-mediated contractions in the circular muscle of the human ileum. Involvement of neurokinin-2 receptors. Maggi, C.A., Giuliani, S., Patacchini, R., Santicioli, P., Theodorsson, E., Barbanti, G., Turini, D., Giachetti, A. Gastroenterology (1992) [Pubmed]
  9. PIP2 signaling in lipid domains: a critical re-evaluation. van Rheenen, J., Achame, E.M., Janssen, H., Calafat, J., Jalink, K. EMBO J. (2005) [Pubmed]
  10. Two nonpeptide tachykinin antagonists act through epitopes on corresponding segments of the NK1 and NK2 receptors. Gether, U., Yokota, Y., Emonds-Alt, X., Brelière, J.C., Lowe, J.A., Snider, R.M., Nakanishi, S., Schwartz, T.W. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  11. Induction of negative hematopoietic regulators by neurokinin-A in bone marrow stroma. Rameshwar, P., Gascón, P. Blood (1996) [Pubmed]
  12. The ligand binding site of the neurokinin 2 receptor. Site-directed mutagenesis and identification of neurokinin A binding residues in the human neurokinin 2 receptor. Bhogal, N., Donnelly, D., Findlay, J.B. J. Biol. Chem. (1994) [Pubmed]
  13. Characterization of the [125I]-neurokinin A binding site in the circular muscle of human colon. Warner, F.J., Comis, A., Miller, R.C., Burcher, E. Br. J. Pharmacol. (1999) [Pubmed]
  14. Tachykinin NK1 and NK2 receptors mediate non-adrenergic non-cholinergic excitatory neuromuscular transmission in the human ileum. Zagorodnyuk, V., Santicioli, P., Turini, D., Maggi, C.A. Neuropeptides (1997) [Pubmed]
  15. Tachykinin receptors on human monocytes: their involvement in rheumatoid arthritis. Brunelleschi, S., Bordin, G., Colangelo, D., Viano, I. Neuropeptides (1998) [Pubmed]
  16. The human neurokinin A (substance K) receptor. Molecular cloning of the gene, chromosome localization, and isolation of cDNA from tracheal and gastric tissues. Gerard, N.P., Eddy, R.L., Shows, T.B., Gerard, C. J. Biol. Chem. (1990) [Pubmed]
  17. 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]
  18. Pharmacological characterization of a new class of nonpeptide neurokinin A antagonists that demonstrate species selectivity. Aharony, D., Buckner, C.K., Ellis, J.L., Ghanekar, S.V., Graham, A., Kays, J.S., Little, J., Meeker, S., Miller, S.C., Undem, B.J. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  19. Regulation of the stimulant actions of neurokinin a and human hemokinin-1 on the human uterus: a comparison with histamine. Pennefather, J.N., Patak, E., Ziccone, S., Lilley, A., Pinto, F.M., Page, N.M., Story, M.E., Grover, S., Candenas, M.L. Biol. Reprod. (2006) [Pubmed]
  20. Facilitatory effects of selective agonists for tachykinin receptors on cholinergic neurotransmission: evidence for species differences. Belvisi, M.G., Patacchini, R., Barnes, P.J., Maggi, C.A. Br. J. Pharmacol. (1994) [Pubmed]
  21. Cannabinoid 1 (CB1) receptors coupled to cholinergic motorneurones inhibit neurogenic circular muscle contractility in the human colon. Hinds, N.M., Ullrich, K., Smid, S.D. Br. J. Pharmacol. (2006) [Pubmed]
  22. The tachykinin NK1 receptor mediates the migration-promoting effect of substance P on human skin fibroblasts in culture. Parenti, A., Amerini, S., Ledda, F., Maggi, C.A., Ziche, M. Naunyn Schmiedebergs Arch. Pharmacol. (1996) [Pubmed]
  23. The species selectivity of chemically distinct tachykinin nonpeptide antagonists is dependent on common divergent residues of the rat and human neurokinin-1 receptors. Jensen, C.J., Gerard, N.P., Schwartz, T.W., Gether, U. Mol. Pharmacol. (1994) [Pubmed]
  24. A new class of high affinity ligands for the neurokinin A NK2 receptor: psi (CH2NR) reduced peptide bond analogues of neurokinin A4-10. Harbeson, S.L., Shatzer, S.A., Le, T.B., Buck, S.H. J. Med. Chem. (1992) [Pubmed]
  25. Tachykinin activation of human monocytes from patients with rheumatoid arthritis: in vitro and ex-vivo effects of cyclosporin A. Lavagno, L., Bordin, G., Colangelo, D., Viano, I., Brunelleschi, S. Neuropeptides (2001) [Pubmed]
  26. Hematopoietic modulation by the tachykinins. Rameshwar, P., Gascón, P. Acta Haematol. (1997) [Pubmed]
  27. A single mutation of the neurokinin-2 (NK2) receptor prevents agonist-induced desensitization. Divergent conformational requirements for NK2 receptor signaling and agonist-induced desensitization in Xenopus oocytes. Nemeth, K., Chollet, A. J. Biol. Chem. (1995) [Pubmed]
  28. Biochemical characterization and solubilization of human NK2 receptor expressed in Chinese hamster ovary cells. Turcatti, G., Ceszkowski, K., Chollet, A. J. Recept. Res. (1993) [Pubmed]
  29. Heterologous desensitization of the human endothelin A and neurokinin A receptors in Xenopus laevis oocytes. Cyr, C.R., Devi, L.A., Rudy, B., Kris, R.M. Receptors & signal transduction. (1996) [Pubmed]
  30. MEN 11420, a potent and selective tachykinin NK2 receptor antagonist in the guinea-pig and human colon. Santicioli, P., Giuliani, S., Patacchini, R., Tramontana, M., Criscuoli, M., Maggi, C.A. Naunyn Schmiedebergs Arch. Pharmacol. (1997) [Pubmed]
  31. Calcium influx and protein kinase C alpha activation mediate arachidonic acid mobilization by the human NK-2 receptor expressed in Chinese hamster ovary cells. Arkinstall, S., Emergy, I., Church, D., Chollet, A., Kawashima, E. FEBS Lett. (1994) [Pubmed]
  32. Isolation and characterisation of the human lung NK-2 receptor gene using rapid amplification of cDNA ends. Graham, A., Hopkins, B., Powell, S.J., Danks, P., Briggs, I. Biochem. Biophys. Res. Commun. (1991) [Pubmed]
  33. Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential. Herpfer, I., Lieb, K. CNS drugs. (2005) [Pubmed]
  34. Pharmacological characterization of ZD6021: a novel, orally active antagonist of the tachykinin receptors. Rumsey, W.L., Aharony, D., Bialecki, R.A., Abbott, B.M., Barthlow, H.G., Caccese, R., Ghanekar, S., Lengel, D., McCarthy, M., Wenrich, B., Undem, B., Ohnmacht, C., Shenvi, A., Albert, J.S., Brown, F., Bernstein, P.R., Russell, K. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  35. Activity of nonpeptide tachykinin antagonists on neurokinin a induced contractions in dog urinary bladder. Rizzo, C.A., Hey, J.A. J. Urol. (2000) [Pubmed]
  36. Glucocorticoids reduce tachykinin NK2 receptor expression in bovine tracheal smooth muscle. Katsunuma, T., Mak, J.C., Barnes, P.J. Eur. J. Pharmacol. (1998) [Pubmed]
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