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Gene Review

Tac1  -  tachykinin 1

Mus musculus

Synonyms: 4930528L02Rik, NK-1, NK1, Nka, Nkna, ...
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Disease relevance of Tac1


Psychiatry related information on Tac1

  • METHODS: Using a communication box system, foot shock stress (FS) and psychological stress (PS) were administered to mice and the degranulation rate of dermal mast cells, the number of SP-positive nerve fibers and changes in SP content were determined [5].
  • We conclude that substance P has an important and specific role in mediating the motivational aspects of opiates and may represent a new pharmacological route for the control of drug abuse [6].
  • Substance P is generally considered an excitatory neurotransmitter related to gut motor activity, although an inhibitory influence of neurokinin-1 (NK1) receptor activation on peristalsis has also been reported [7].
  • The influence of substance P on nociception depended on the individual mouse's sensitivity to pain (control response latency) [8].
  • However, in contrast to enkephalin immunoreactivity, immunolabeling for substance P was not significantly decreased at this time-point in the internal pallidum, a finding reminiscent of early grades of Huntington's disease [9].

High impact information on Tac1


Chemical compound and disease context of Tac1

  • Although it is well established that substance P (SP) interacts with the neurokinin 1 receptor (NK1R) to initiate neurogenic inflammation, the mechanisms that terminate inflammation are unknown [2].
  • Concentrations of immunoreactive SP, NKA, and CGRP were measured in extracts of the eczema ears (n = 26), whereas extracts of the opposite ears were used as controls [15].
  • Because METH augments striatal substance P (SP) levels, we hypothesized that this neuropeptide plays a role in methamphetamine-induced toxicity and neural damage in the striatum [16].
  • Neurokinin-1 receptors are involved in behavioral responses to high-intensity heat stimuli and capsaicin-induced hyperalgesia in mice [17].
  • Furthermore, pretreatment of mice with CP-96345 (2.5 mg/kg ip), an antagonist of the neurokinin-1 (NK(1)) receptor, protected mice against lung inflammation caused by H(2)S [18].

Biological context of Tac1


Anatomical context of Tac1


Associations of Tac1 with chemical compounds

  • The present study examines mice with a targeted deletion of the Tac1 gene, which encodes the neuropeptides substance P and neurokinin A, in animal models relevant to depressive illness and anxiety [23].
  • The excitatory neurotransmitter glutamate coexists with the peptide known as substance P in primary afferents that respond to painful stimulation [24].
  • Noradrenaline (NA), a key neurotransmitter of the endogenous pain inhibitory system, acutely inhibits nociceptive transmission (including that mediated by substance P), potentiates opioid analgesia, and underlies part of the antinociceptive effects of the widely prescribed tricyclic antidepressants [25].
  • This elevated plasma leak was attenuated by recombinant NEP or the NK1R antagonist SR140333, and is thus caused by diminished degradation of SP [2].
  • The highly specific SP receptor antagonist, CP-96,345, completely inhibited the effect of SP but not SOM on IgG2a release [19].

Physical interactions of Tac1


Enzymatic interactions of Tac1

  • D. melanogaster NEP2 also differs from human NEP in the manner in which the peptidase cleaves the tachykinin, GPSGFYGVR-amide [31].

Co-localisations of Tac1


Regulatory relationships of Tac1

  • Specific NK-1 receptor antagonists blocked all tachykinin-induced, IFN-gamma secretion [26].
  • The activity of neuromedin K was blocked by the substance P antagonist [D-Pro2D-Trp7.9]substance P at doses of antagonist which effectively blocked the activity of the other tachykinins [33].
  • Correspondingly, the addition of SP to these cells resulted in a rapid increase in intracellular Ca2+ levels that could be specifically blocked by an NK-2R antagonist [34].
  • It was discovered that SP regulates SOM synthesis [35].
  • PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors [36].

Other interactions of Tac1

  • We conclude that when unopposed by NA, substance P acting at the NK1 receptor causes chronic thermal hyperalgesia, and that the reduced opioid efficacy associated with a lack of NA is due to increased NK1-receptor stimulation [25].
  • In contrast, toxin A administration in Crh(-/-) mice fails to result in an increased SP content [37].
  • At birth, transgenic DRG showed increased neuron numbers, and displayed a normal proportion of neurons expressing substance P, calcitonin gene-related peptide and the NT3 receptor trkC [38].
  • Also, SP and SOM may be components of a natural circuit within inflammation that regulates IFN-gamma production [26].
  • There are three distinct tachykinin receptors, called NK-1, NK-2 and NK-3 [26].

Analytical, diagnostic and therapeutic context of Tac1


  1. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. De Felipe, C., Herrero, J.F., O'Brien, J.A., Palmer, J.A., Doyle, C.A., Smith, A.J., Laird, J.M., Belmonte, C., Cervero, F., Hunt, S.P. Nature (1998) [Pubmed]
  2. Neutral endopeptidase (EC terminates colitis by degrading substance P. Sturiale, S., Barbara, G., Qiu, B., Figini, M., Geppetti, P., Gerard, N., Gerard, C., Grady, E.F., Bunnett, N.W., Collins, S.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  3. Characterization of the endokinins: human tachykinins with cardiovascular activity. Page, N.M., Bell, N.J., Gardiner, S.M., Manyonda, I.T., Brayley, K.J., Strange, P.G., Lowry, P.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  4. IL-12 induction of mRNA encoding substance P in murine macrophages from the spleen and sites of inflammation. Arsenescu, R., Blum, A.M., Metwali, A., Elliott, D.E., Weinstock, J.V. J. Immunol. (2005) [Pubmed]
  5. Role of substance P in stress-derived degranulation of dermal mast cells in mice. Kawana, S., Liang, Z., Nagano, M., Suzuki, H. J. Dermatol. Sci. (2006) [Pubmed]
  6. Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Murtra, P., Sheasby, A.M., Hunt, S.P., De Felipe, C. Nature (2000) [Pubmed]
  7. Ava[L-Pro9,N-MeLeu10] substance P(7-11) (GR 73632) and Sar9, Met(O2)11 increase distention-induced peristalsis through activation of neurokinin-1 receptors on smooth muscle and interstitial cells of cajal. Nieuwmeyer, F., Ye, J., Huizinga, J.D. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  8. Substance P: does it produce analgesia or hyperalgesia? Oehme, P., Hilse, H., Morgenstern, E., Göres, E. Science (1980) [Pubmed]
  9. Early effects of intrastriatal injections of quinolinic acid on microtubule-associated protein-2 and neuropeptides in rat basal ganglia. Bordelon, Y.M., Chesselet, M.F. Neuroscience (1999) [Pubmed]
  10. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Razavi, R., Chan, Y., Afifiyan, F.N., Liu, X.J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., Santamaria, P., Driver, J.P., Serreze, D., Salter, M.W., Dosch, H.M. Cell (2006) [Pubmed]
  11. Interaction with vesicle luminal protachykinin regulates surface expression of delta-opioid receptors and opioid analgesia. Guan, J.S., Xu, Z.Z., Gao, H., He, S.Q., Ma, G.Q., Sun, T., Wang, L.H., Zhang, Z.N., Lena, I., Kitchen, I., Elde, R., Zimmer, A., He, C., Pei, G., Bao, L., Zhang, X. Cell (2005) [Pubmed]
  12. A neuropeptide courier for delta-opioid receptors? Julius, D., Basbaum, A.I. Cell (2005) [Pubmed]
  13. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Ernfors, P., Lee, K.F., Kucera, J., Jaenisch, R. Cell (1994) [Pubmed]
  14. Reduced antinociception and plasma extravasation in mice lacking a neuropeptide Y receptor. Naveilhan, P., Hassani, H., Lucas, G., Blakeman, K.H., Hao, J.X., Xu, X.J., Wiesenfeld-Hallin, Z., Thorén, P., Ernfors, P. Nature (2001) [Pubmed]
  15. Tachykinins and calcitonin gene-related peptide in oxazolone-induced allergic contact dermatitis in mice. Ek, L., Theodorsson, E. J. Invest. Dermatol. (1990) [Pubmed]
  16. Neurokinin-1 (NK-1) receptor antagonists abrogate methamphetamine-induced striatal dopaminergic neurotoxicity in the murine brain. Yu, J., Cadet, J.L., Angulo, J.A. J. Neurochem. (2002) [Pubmed]
  17. Neurokinin-1 receptors are involved in behavioral responses to high-intensity heat stimuli and capsaicin-induced hyperalgesia in mice. Mansikka, H., Shiotani, M., Winchurch, R., Raja, S.N. Anesthesiology (1999) [Pubmed]
  18. Role of substance P in hydrogen sulfide-induced pulmonary inflammation in mice. Bhatia, M., Zhi, L., Zhang, H., Ng, S.W., Moore, P.K. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  19. Substance P and somatostatin can modulate the amount of IgG2a secreted in response to schistosome egg antigens in murine schistosomiasis mansoni. Blum, A.M., Metwali, A., Mathew, R.C., Elliott, D., Weinstock, J.V. J. Immunol. (1993) [Pubmed]
  20. Tachykinin receptors of the NK1 type (substance P) coupled positively to phospholipase C on cortical astrocytes from the newborn mouse in primary culture. Torrens, Y., Daguet De Montety, M.C., el Etr, M., Beaujouan, J.C., Glowinski, J. J. Neurochem. (1989) [Pubmed]
  21. Specific binding of substance P aminoterminal heptapeptide [SP(1-7)] to mouse brain and spinal cord membranes. Igwe, O.J., Kim, D.C., Seybold, V.S., Larson, A.A. J. Neurosci. (1990) [Pubmed]
  22. A role for mesenchyme-derived tachykinins in tooth and mammary gland morphogenesis. Weil, M., Itin, A., Keshet, E. Development (1995) [Pubmed]
  23. Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene. Bilkei-Gorzo, A., Racz, I., Michel, K., Zimmer, A. J. Neurosci. (2002) [Pubmed]
  24. Primary afferent tachykinins are required to experience moderate to intense pain. Cao, Y.Q., Mantyh, P.W., Carlson, E.J., Gillespie, A.M., Epstein, C.J., Basbaum, A.I. Nature (1998) [Pubmed]
  25. The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline. Jasmin, L., Tien, D., Weinshenker, D., Palmiter, R.D., Green, P.G., Janni, G., Ohara, P.T. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  26. Substance P modulates antigen-induced, IFN-gamma production in murine Schistosomiasis mansoni. Blum, A.M., Metwali, A., Cook, G., Mathew, R.C., Elliott, D., Weinstock, J.V. J. Immunol. (1993) [Pubmed]
  27. Substance-P-mediated intestinal inflammation: inhibitory effects of CP 96,345 and SMS 201-995. Kataeva, G., Agro, A., Stanisz, A.M. Neuroimmunomodulation (1994) [Pubmed]
  28. Ventral striatopallidal oxytocin and vasopressin V1a receptors in the monogamous prairie vole (Microtus ochrogaster). Lim, M.M., Murphy, A.Z., Young, L.J. J. Comp. Neurol. (2004) [Pubmed]
  29. Intrathecally administered spermine produces the scratching, biting and licking behaviour in mice. Tan-No, K., Taira, A., Wako, K., Niijima, F., Nakagawasai, O., Tadano, T., Sakurada, C., Sakurada, T., Kisara, K. Pain (2000) [Pubmed]
  30. An immobilized metal ion affinity adsorption and scintillation proximity assay for receptor-stimulated phosphoinositide hydrolysis. Liu, J.J., Hartman, D.S., Bostwick, J.R. Anal. Biochem. (2003) [Pubmed]
  31. Drosophila melanogaster NEP2 is a new soluble member of the neprilysin family of endopeptidases with implications for reproduction and renal function. Thomas, J.E., Rylett, C.M., Carhan, A., Bland, N.D., Bingham, R.J., Shirras, A.D., Turner, A.J., Isaac, R.E. Biochem. J. (2005) [Pubmed]
  32. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. Edvinsson, L., Ekman, R., Jansen, I., McCulloch, J., Uddman, R. J. Cereb. Blood Flow Metab. (1987) [Pubmed]
  33. Tachykinin-like central activity of neuromedin K in mice. Vaught, J.L., Post, L.J., Jacoby, H.I., Wright, D. Eur. J. Pharmacol. (1984) [Pubmed]
  34. Substance P induction of murine keratinocyte PAM 212 interleukin 1 production is mediated by the neurokinin 2 receptor (NK-2R). Song, I.S., Bunnett, N.W., Olerud, J.E., Harten, B., Steinhoff, M., Brown, J.R., Sung, K.J., Armstrong, C.A., Ansel, J.C. Exp. Dermatol. (2000) [Pubmed]
  35. Substance P regulates somatostatin expression in inflammation. Blum, A.M., Elliott, D.E., Metwali, A., Li, J., Qadir, K., Weinstock, J.V. J. Immunol. (1998) [Pubmed]
  36. PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors. Zhao, A., Shea-Donohue, T. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  37. Corticotropin-releasing hormone (CRH) requirement in Clostridium difficile toxin A-mediated intestinal inflammation. Anton, P.M., Gay, J., Mykoniatis, A., Pan, A., O'Brien, M., Brown, D., Karalis, K., Pothoulakis, C. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  38. Limb proprioceptive deficits without neuronal loss in transgenic mice overexpressing neurotrophin-3 in the developing nervous system. Ringstedt, T., Kucera, J., Lendahl, U., Ernfors, P., Ibáñez, C.F. Development (1997) [Pubmed]
  39. Tachykinin expression in cartilage and function in human articular chondrocyte mechanotransduction. Millward-Sadler, S.J., Mackenzie, A., Wright, M.O., Lee, H.S., Elliot, K., Gerrard, L., Fiskerstrand, C.E., Salter, D.M., Quinn, J.P. Arthritis Rheum. (2003) [Pubmed]
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