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HGNC Approved Gene Symbol: TAC1
Cytogenetic location: 7q21.3 Genomic coordinates (GRCh38): 7:97,732,086-97,740,472 (from NCBI)
Tachykinins are a family of peptides that have similar biologic activities and share a common C-terminal sequence, phe-X-gly-leu-met-NH2, but have distinct N-terminal sequences that convey receptor specificities. Members of this family include substance P, neurokinin A (also known as substance K), and neurokinin B (TAC3; 162330). The TAC1 gene encodes both substance P and neurokinin A (Krause et al., 1987).
Krause et al. (1987) showed that 3 forms of preprotachykinin mRNAs, designated alpha, beta, and gamma, arise by alternative splicing events in rat. The beta and gamma forms encode both substance P and neurokinin A, while the alpha form contains only the substance P sequence.
Using probes derived from the cloned human gene and a panel of rodent-human somatic cell hybrids, Bonner et al. (1987) assigned the NKNA gene to chromosome 7q21-q22.
Bahary et al. (1991) mapped the homologous gene to mouse chromosome 6.
Mesenchymal stem cells (MSCs) primarily reside in adult bone marrow and can generate functional neuronal cells. Human MSC-derived neuronal cells express the TAC1 transcript, but not its peptide product, substance P, unless stimulated with IL1A (147760). Using microRNA (miRNA)-specific bioarrays, Greco and Rameshwar (2007) found that the miRNAs MIRN130A (610175), MIRN206 (611599), and MIRN302A were downregulated by IL1A in MSC-derived neuronal cells. They identified putative binding sites for these miRNAs within the 3-prime UTR of TAC1, and reporter gene assays confirmed the MIRN130A and MIRN206 sites. Specific inhibition of MIRN130A and MIRN206 in MSC-derived neuronal cells resulted in substance P synthesis and release. Greco and Rameshwar (2007) concluded that IL1A alleviates translational repression of TAC1 mRNA through negative effects on miRNAs.
Using several animal models, Hong et al. (2009) showed that substance P is an injury-inducible factor that acts early in the wound healing process to induce mobilization of Cd29 (ITGB1; 135630)-positive stromal-like cells that were similar to bone marrow stromal cells (BMSCs). Using human BMSCs, Hong et al. (2009) found that substance P stimulated transmigration, proliferation, activation of ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948), and nuclear translocation of beta-catenin (CTNNB1; 116806) in vitro. Hong et al. (2009) concluded that substance P mobilizes CD29-positive stromal-like cells to participate in wound healing.
In mice, Huang et al. (2019) showed that spinal neurons marked by coexpression of Tac1 and Lbx1 (604255) drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that, in humans, produce sustained pain, without affecting any of the reflexive defensive reactions that were tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei. Consistently, spinal Tac1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomic and functional segregation observed at the spinal level also applies to primary sensory neurons. For example, in response to noxious mechanical stimuli, Mrgprd (607231)- and Trpv1 (602076)-positive nociceptors are required to elicit reflexive and coping responses, respectively. Huang et al. (2019) concluded that their study revealed a fundamental subdivision within the cutaneous somatosensory system, and challenged the validity of using reflexive defensive responses to measure sustained pain.
Cao et al. (1998) disrupted the mouse preprotachykinin A gene, which encodes both substance P and neurokinin A. The behavioral response to mildly painful stimuli was intact in mutant mice, but the response to moderate to intense pain was significantly reduced. Neurogenic inflammation, which results from peripheral release of substance P and neurokinin A, was almost absent in the mutant mice. The contribution of substance P and neurokinin A was neither modality- nor tissue-specific; pain behaviors evoked by thermal, mechanical, and chemical stimulation of somatic and visceral tissues were all reduced in the mutant mice. The authors concluded that the release of tachykinins from primary afferent pain-sensing receptors (nociceptors) is required to produce moderate to intense pain. Cao et al. (1998) proposed that glutamate is the neurotransmitter for basal pain response, that substance P and neurokinin A are released with higher stimuli, and that at the highest intensities, an undefined system comes into play.
In the mouse, the tachykinins are encoded by the genes Tac1 and Tac2. Neurokinin A, neuropeptide K, and neuropeptide gamma, as well as substance P, are produced from the Tac1 gene as a result of differential splicing and posttranslational processing. Tac2 produces the peptide neurokinin B. Substance P and substance K are produced in nociceptive primary sensory neurons and in many brain regions involved in pain signaling. By targeted deletion of the Tac1 gene, Zimmer et al. (1998) showed that mice that cannot produce these peptides displayed no significant pain responses following formalin injection and had an increased pain threshold in the hotplate test. On the other hand, they reacted normally in some other tests. The results demonstrated that substance B and/or substance K have essential functions in specific responses to pain.
Liu et al. (1999) reported that mice with disruption of the preprotachykinin A gene were resistant to kainate excitotoxicity. The mice showed a reduction in the duration and severity of induced seizures, and both necrosis and apoptosis of hippocampal neurons were prevented. Although kainate induced the expression of Bax (600040) and caspase-3 (CASP3; 600636) in the hippocampus of wildtype mice, these critical intracellular mediators of cell death pathways were not altered by kainate injection of the mutant mice. These results indicated that the reduction of seizure activity and the neuroprotection observed in preprotachykinin A-null mice are caused by the extinction of a substance P/neurokinin A-mediated signaling pathway that is activated by seizures. The authors suggested that these neurokinins are critical to the control of hippocampal excitability, hippocampal seizures, and hippocampal vulnerability.
Troger et al. (2001) investigated neurotransmitter behavior in the streptozotocin-induced diabetic rat retina. They found reduction of substance P and vasoactive intestinal polypeptide (VIP; 192320), in contrast to the previously established elevations in GABA and glycine in the early stages of diabetic retinopathy. The authors stated that the reductions in substance P and VIP are noteworthy for the following reasons: first, both peptides are known to modulate excitability of inner retinal neurons; second, the reductions might be the result of excitotoxin damage; and third, the finding may help explain why retinal neovascularization does not occur in this animal model, although Vegf (192240) is massively upregulated, as substance P is a very potent vascular growth factor.
Using immunohistochemistry, Svensson et al. (2005) detected increased levels of SP in vaginal tissue early after infection of female mice with genital herpes simplex virus (HSV)-2. A modest, but statistically significant, inhibitory effect of SP on HSV-2 infection was observed in vitro. Mice lacking the SP receptor, Nk1r (TACR1; 162323), showed enhanced viral replication, including in the central nervous system, and reduced viral clearance associated with HSV-2 dose-dependent accumulation of Mip1a (CCL3; 182283) and impaired local natural killer cell function. Vaccination of Nk1r -/- and wildtype mice with an attenuated HSV-2 strain showed that SP signaling was not required for protection against HSV-2 challenge, and HSV-2-specific T cells secreting Ifng (147570) were present in both Nk1r -/- and wildtype mice. Svensson et al. (2005) concluded that HSV-2 infection induces SP expression in vagina and that NK1R signaling contributes to innate resistance to infection.
African naked mole-rats lack substance P and calcitonin gene-related peptide (CGRP; 114130) in cutaneous sensory fibers. Park et al. (2008) showed that these animals were insensitive to capsaicin and acid injection and lacked thermal hyperalgesia after peripheral inflammation. Infusion of substance P rescued thermal hyperalgesia and sensitivity to capsaicin, but did not rescue sensitivity to acid. Electrophysiologic recordings showed that naked mole-rat nociceptors responded to capsaicin, but the functional connectivity of capsaicin-sensitive sensory fibers in the spinal cord dorsal horn was substantially different than that found in other rodents.
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Bonner, T. I., Young, A. C., de Miguel, C., Detera-Wadleigh, S., Modi, W. S., O'Brien, S. J. The chromosomal location of the two human tackykinin (sic) genes: human substance P and neurokinin K. (Abstract) Cytogenet. Cell Genet. 46: 584 only, 1987.
Cao, Y. Q., Mantyh, P. W., Carlson, E. J., Gillespie, A.-M., Epstein, C. J., Basbaum, A. I. Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392: 390-393, 1998. [PubMed: 9537322] [Full Text: https://doi.org/10.1038/32897]
Greco, S. J., Rameshwar, P. MicroRNAs regulate synthesis of the neurotransmitter substance P in human mesenchymal stem cell-derived neuronal cells. Proc. Nat. Acad. Sci. 104: 15484-15489, 2007. [PubMed: 17855557] [Full Text: https://doi.org/10.1073/pnas.0703037104]
Hong, H. S., Lee, J., Lee, E., Kwon, Y. S., Lee, E., Ahn, W., Jiang, M. H., Kim, J. C., Son, Y. A new role of substance P as an injury-inducible messenger for mobilization of CD29+ stromal-like cells. Nature Med. 15: 425-435, 2009. [PubMed: 19270709] [Full Text: https://doi.org/10.1038/nm.1909]
Huang, T., Lin, S.-H., Malewicz, N. M., Zhang, Y., Zhang, Y., Goulding, M., LaMotte, R. H., Ma, Q. Identifying the pathways required for coping behaviours associated with sustained pain. Nature 565: 86-90, 2019. [PubMed: 30532001] [Full Text: https://doi.org/10.1038/s41586-018-0793-8]
Krause, J. E., Chirgwin, J. M., Carter, M. S., Xu, Z. S., Hershey, A. D. Three rat preprotachykinin mRNAs encode the neuropeptides substance P and neurokinin A. Proc. Nat. Acad. Sci. 84: 881-885, 1987. [PubMed: 2433692] [Full Text: https://doi.org/10.1073/pnas.84.3.881]
Liu, H., Cao, Y., Basbaum, A. I., Mazarati, A. M, Sankar, R., Wasterlain, C. G. Resistance to excitotoxin-induced seizures and neuronal death in mice lacking the preprotachykinin A gene. Proc. Nat. Acad. Sci. 96: 12096-12101, 1999. [PubMed: 10518582] [Full Text: https://doi.org/10.1073/pnas.96.21.12096]
Park, T. J., Lu, Y., Juttner, R., Smith, E. St. J., Hu, J., Brand, A., Wetzel, C., Milenkovic, N., Erdmann, B., Heppenstall, P. A., Laurito, C. E., Wilson, S. P., Lewin, G. R. Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber). PLoS Biol. 6: e13, 2008. Note: Electronic Article. [PubMed: 18232734] [Full Text: https://doi.org/10.1371/journal.pbio.0060013]
Svensson, A., Kaim, J., Mallard, C., Olsson, A., Brodin, E., Hokfelt, T., Eriksson, K. Neurokinin 1 receptor signaling affects the local innate immune defense against genital herpes virus infection. J. Immun. 175: 6802-6811, 2005. [PubMed: 16272337] [Full Text: https://doi.org/10.4049/jimmunol.175.10.6802]
Troger, J., Neyer, S., Heufler, C., Huemer, H., Schmid, E., Griesser, U., Kralinger, M., Kremser, B., Baldissera, I., Kieselbach, G. Substance P and vasoactive intestinal polypeptide in the streptozotocin-induced diabetic rat retina. Invest. Ophthal. Vis. Sci. 42: 1045-1050, 2001. [PubMed: 11274084]
Zimmer, A., Zimmer, A. M., Baffi, J., Usdin, T., Reynolds, K., Konig, M., Palkovits, M., Mezey, E. Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc. Nat. Acad. Sci. 95: 2630-2635, 1998. [PubMed: 9482938] [Full Text: https://doi.org/10.1073/pnas.95.5.2630]