Substance P

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tachykinin, precursor 1
Spacefilling model of substance P
Identifiers
SymbolTAC1
Alt. symbolsTAC2, NKNA
Entrez6863
HUGO11517
OMIM162320
RefSeqNM_003182
UniProtP20366
Other data
LocusChr. 7 q21-q22
Template:Chembox E number
Substance P
Error creating thumbnail: File missing
Identifiers
ChemSpider
ECHA InfoCard Lua error in Module:Wikidata at line 879: attempt to index field 'wikibase' (a nil value). Lua error in Module:Wikidata at line 879: attempt to index field 'wikibase' (a nil value).
MeSH Substance+P
Properties
C63H98N18O13S
Molar mass 1347.63 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

In the field of neuroscience, substance P (SP) is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator.[1][2] It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows[citation needed]:

Substance P is released from the terminals of specific sensory nerves, it is found in the brain and spinal cord, and is associated with inflammatory processes and pain.

Discovery

Substance P was originally discovered in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro.[3] Its tissue distribution and biologic actions were further investigated over the following decades.[1] In 1983, NKA (previously known as substance K or neuromedin L) was isolated from porcine spinal cord and was also found to stimulate intestinal contraction.[4]

Receptor

The endogenous receptor for Substance P is neurokinin 1 receptor (NK1-receptor, NK1R).[5] It belongs to the tachykinin receptor sub-family of GPCRs.[6] Other neurokinin subtypes and neurokinin receptors that interact with SP have also been reported. Amino acid residues that are responsible for the binding of SP and its antagonists are present in the extracellular loops and transmembrane regions of NK-1. Binding of SP to NK-1 results in internalization by the clathrin-dependant mechanism to the acidified endosomes where the complex disassociates. SP is subsequently degraded and NK-1 is re-expressed on the cell surface.[7] Substance P and the NK1 receptor are widely distributed in the brain and are specifically found in brain regions that regulate emotion (hypothalamus, amygdala, and the periaqueductal gray).[8] They are also found in close association with 5-hydroxytryptamine (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs.[9] The SP receptor promoter contains regions that are sensitive to cAMP, AP-1, AP-4, CEBPB[10] and epidermal growth factor. Because these regions are related to complexed signal transduction pathways mediated by cytokines, it has been proposed that cytokines and neurotropic factors can induce NK-1. SP can also induce the cytokines that are capable of inducing NK-1 transcription factors.[11]

Function

Substance P is an important element in pain perception. The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system. Substance P coexists with the excitatory neurotransmitter glutamate in primary afferents that respond to painful stimulation.[12] SP has been associated with the regulation of mood disorders, anxiety, stress,[13] reinforcement,[14] neurogenesis,[15] respiratory rhythm,[16] neurotoxicity, nausea/emesis,[17] pain and nociception.[18] Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle and joints. It is proposed that this release is involved in neurogenic inflammation which is a local inflammatory response to certain types of infection or injury.[19] The regulatory function of SP also involves the regulation of its high-affinity receptor, NK-1. Substance P receptor antagonists may have important therapeutic applications in the treatment of a variety of stress-related illnesses, in addition to their potential as analgesics.

Vomiting

The vomiting center in the brainstem contains high concentrations of substance P and its receptor, in addition to other neurotransmitters such as choline, histamine, dopamine, serotonin, and opioids. Their activation stimulates the vomiting reflex. Different emetic pathways exist, and substance P/NK1R appears to be within the final common pathway to regulate vomiting.[20] Substance P antagonist (SPA) aprepitant is available in the market in the treatment of chemotherapy-induced nausea/emesis.

Pain

Substance P is involved in nociception, transmitting information about tissue damage from peripheral receptors to the central nervous system to be converted to the sensation of pain. It has been theorized that it plays a part in fibromyalgia. Capsaicin has been shown to reduce the levels of Substance P probably by reducing the number of C-fibre nerves or causing these nerves to be more tolerant. Thus, Capsaicin is clinically used as an analgesic and anti-inflammatory agent to relieve pain associated with arthritis and many types of neuralgia. A role of substance P and NKA in nociception is suggested by the reduction in response thresholds to noxious stimuli by central administration of NK1 and NK2 agonists. Based on recent studies, it was proposed that NK1, and possibly the NK2 receptor antagonists could be developed as analgesic drugs. It has been studied that the mice carrying a disruption of the gene encoding SP/NKA, show severely reduced nociceptive pain responses when the stimuli are moderate to intense. Pain behaviors induced by mechanical, thermal and chemical stimulation of somatic and visceral tissues were reduced in the mutant mice lacking SP/NKA. However, it has been proposed that the importance of SP and NKA in animal's pain response apply only to a certain 'window' of pain intensities and when the intensity of the pain stimuli is further increased, the responses of the knockout mice is not severely different from the wild-type mice.[12]

Cell growth

Substance P has been known to stimulate cell growth in culture,[21] and it was shown that Substance P could promote wound healing of non-healing ulcers in humans.[22] It has also been shown to reverse diabetes in mice.[23][24]

Vasodilation

Substance P also has effects as a potent vasodilator. Substance P-induced vasodilatation is dependent on nitric oxide release.[25] Substance P is involved in the axon reflex-mediated vasodilatation to local heating and wheal and flare reaction. It has been shown that vasodilatation to substance P is dependent on the NK1 receptor located on the endothelium. In contrast to other neuropeptides studied in human skin, substance P-induced vasodilatation has been found to decline during continuous infusion. This possibly suggest an internalization of neurokinin-1 (NK1).[26] As is typical with many vasodilators, it also has bronchoconstrictive properties, administered through the non-adrenergic, non-cholinergic nervous system (branch of the vagal system).

Clinical significance

Eczema

High levels of BDNF and Substance P have been found associated with increased itching in eczema.[27][28]

Gastrointestinal infection

Entamoeba histolytica is a single-celled parasitic protozoan that infects the lower gastrointestinal tract of humans. The symptoms of infection are diarrhea, constipation, and abdominal pain.[29][30] This protozoan was found to secrete serotonin[31] as well as substance P and neurotensin.[32]

Deficiency

Naked mole rats lack Substance P and do not feel pain when painful stimuli are administered to the skin.[33][34] New studies have shown that when the function of SP is genetically disrupted in mice, the animals demonstrated reduced responses to painful stimuli. Moreover, the response to capsaicin was absent or severely reduced in knockout mice.[12]

References

  1. ↑ 1.0 1.1 Harrison S, Geppetti P (2001). "Substance p". The International Journal of Biochemistry & Cell Biology. 33 (6): 555–76. doi:10.1016/S1357-2725(01)00031-0. PMID 11378438. Unknown parameter |month= ignored (help)
  2. ↑ Datar P, Srivastava S, Coutinho E, Govil G (2004). "Substance P: structure, function, and therapeutics". Current topics in medicinal chemistry. 4 (1): 75–103. doi:10.2174/1568026043451636. PMID 14754378.
  3. ↑ V Euler US, Gaddum JH (1931). "An unidentified depressor substance in certain tissue extracts". The Journal of Physiology. 72 (1): 74–87. PMC 1403098. PMID 16994201. Unknown parameter |month= ignored (help)
  4. ↑ Panula P, Hadjiconstantinou M, Yang HY, Costa E (1983). "Immunohistochemical localization of bombesin/gastrin-releasing peptide and substance P in primary sensory neurons". The Journal of Neuroscience : the official journal of the Society for Neuroscience. 3 (10): 2021–9. PMID 6194276. Unknown parameter |month= ignored (help)
  5. ↑ Gerard NP, Garraway LA, Eddy RL Jr, Shows TB, Iijima H, Paquet JL, Gerard C (1991). "Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones". Biochemistry. 30 (44): 10640–6. doi:10.1021/bi00108a006. PMID 1657150. Unknown parameter |month= ignored (help)
  6. ↑ Maggi CA (1995). "The mammalian tachykinin receptors". Gen. Pharmacol. 26 (5): 911–44. doi:10.1016/0306-3623(94)00292-U. PMID 7557266.
  7. ↑ Grady EF, Garland AM, Gamp PD, Lovett M, Payan DG, Bunnett NW (1995). "Delineation of the endocytic pathway of substance P and its seven-transmembrane domain NK1 receptor". Molecular Biology of the Cell. 6 (5): 509–24. PMC 301212. PMID 7545030. Unknown parameter |month= ignored (help)
  8. ↑ Yip J, Chahl LA (2001). "Localization of NK1 and NK3 receptors in guinea-pig brain". Regulatory peptides. 98 (1–2): 55–62. doi:10.1016/S0167-0115(00)00228-7. PMID 11179779. Unknown parameter |month= ignored (help)
  9. ↑ Gobbi G, Cassano T, Radja F, Morgese MG, Cuomo V, Santarelli L, Hen R, Blier P (2007). "Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function". European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 17 (5): 328–38. doi:10.1016/j.euroneuro.2006.07.004. PMID 16950604. Unknown parameter |month= ignored (help)
  10. ↑ Kovács KA, Steinmann M, Magistretti PJ, Halfon O, Cardinaux JR (2006). "C/EBPbeta couples dopamine signalling to substance P precursor gene expression in striatal neurones". Journal of Neurochemistry. 98 (5): 1390–9. doi:10.1111/j.1471-4159.2006.03957.x. PMID 16771829. Unknown parameter |month= ignored (help)
  11. ↑ Rameshwar P (1997). "Substance P: a regulatory neuropeptide for hematopoiesis and immune functions". Clinical Immunology and Immunopathology. 85 (2): 129–33. doi:10.1006/clin.1997.4446. PMID 9344694. Unknown parameter |month= ignored (help)
  12. ↑ 12.0 12.1 12.2 De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP (1998). "Altered nociception, analgesia and aggression in mice lacking the receptor for substance P". Nature. 392 (6674): 394–7. doi:10.1038/32904. PMID 9537323. Unknown parameter |month= ignored (help)
  13. ↑ Ebner K, Singewald N (2006). "The role of substance P in stress and anxiety responses". Amino acids. 31 (3): 251–72. doi:10.1007/s00726-006-0335-9. PMID 16820980. Unknown parameter |month= ignored (help)
  14. ↑ Huston JP, Hasenöhrl RU, Boix F, Gerhardt P, Schwarting RK (1993). "Sequence-specific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity". Psychopharmacology. 112 (2–3): 147–62. doi:10.1007/BF02244906. PMID 7532865.
  15. ↑ Park SW, Yan YP, Satriotomo I, Vemuganti R, Dempsey RJ (2007). "Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions". Journal of neurosurgery. 107 (3): 593–9. doi:10.3171/JNS-07/09/0593. PMID 17886560. Unknown parameter |month= ignored (help)
  16. ↑ Bonham AC (1995). "Neurotransmitters in the CNS control of breathing". Respiration physiology. 101 (3): 219–30. doi:10.1016/0034-5687(95)00045-F. PMID 8606995. Unknown parameter |month= ignored (help)
  17. ↑ Hesketh PJ (2001). "Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting". Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 9 (5): 350–4. doi:10.1007/s005200000199. PMID 11497388. Unknown parameter |month= ignored (help)
  18. ↑ Zubrzycka M, Janecka A (2000). "Substance P: transmitter of nociception (Minireview)". Endocrine regulations. 34 (4): 195–201. PMID 11137976. Unknown parameter |month= ignored (help)
  19. ↑ Donkin JJ, Turner RJ, Hassan I, Vink R (2007). "Substance P in traumatic brain injury". Progress in brain research. 161: 97–109. doi:10.1016/S0079-6123(06)61007-8. PMID 17618972.
  20. ↑ Hornby PJ (2001). "Central neurocircuitry associated with emesis". The American Journal of Medicine. 111 Suppl 8A: 106S–112S. doi:10.1016/S0002-9343(01)00849-X. PMID 11749934. Unknown parameter |month= ignored (help)
  21. ↑ Reid TW, Murphy CJ, Iwahashi CK, Foster BA, Mannis MJ (1993). "Stimulation of epithelial cell growth by the neuropeptide substance P". Journal of Cellular Biochemistry. 52 (4): 476–85. doi:10.1002/jcb.240520411. PMID 7693729. Unknown parameter |month= ignored (help)
  22. ↑ Brown SM, Lamberts DW, Reid TW, Nishida T, Murphy CJ (1997). "Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike growth factor 1". Archives of Ophthalmology. 115 (7): 926–7. PMID 9230840. Unknown parameter |month= ignored (help)
  23. ↑ Motluk A, Geddes L (2005-12-15). "Breakthrough sheds light on cause of diabetes". Health. New Scientist. Retrieved 2008-11-01.
  24. ↑ Tsui H, Razavi R, Chan Y, Yantha J, Dosch HM (2007). "'Sensing' autoimmunity in type 1 diabetes". Trends in Molecular Medicine. 13 (10): 405–13. doi:10.1016/j.molmed.2007.07.006. PMID 17900987. Unknown parameter |month= ignored (help)
  25. ↑ Bossaller C, Reither K, Hehlert-Friedrich C, Auch-Schwelk W, Graf K, Gräfe M, Fleck E (1992). "In vivo measurement of endothelium-dependent vasodilation with substance P in man". Herz. 17 (5): 284–90. PMID 1282120. Unknown parameter |month= ignored (help)
  26. ↑ Wong BJ, Tublitz NJ, Minson CT (2005). "Neurokinin-1 receptor desensitization to consecutive microdialysis infusions of substance P in human skin". The Journal of Physiology. 568 (Pt 3): 1047–56. doi:10.1113/jphysiol.2005.095372. PMC 1464169. PMID 16123103. Unknown parameter |month= ignored (help)
  27. ↑ Hon KL, Lam MC, Wong KY, Leung TF, Ng PC (2007). "Pathophysiology of nocturnal scratching in childhood atopic dermatitis: the role of brain-derived neurotrophic factor and substance P". The British Journal of Dermatology. 157 (5): 922–5. doi:10.1111/j.1365-2133.2007.08149.x. PMID 17725670. Unknown parameter |month= ignored (help)
  28. ↑ Steinitz H (1979). "[Chronic recurrent intestinal amebiasis in Israel (author's transl)]". Leber, Magen, Darm (in German). 9 (4): 175–9. PMID 491812.
  29. ↑ Stark D, van Hal S, Marriott D, Ellis J, Harkness J (2007). "Irritable bowel syndrome: a review on the role of intestinal protozoa and the importance of their detection and diagnosis". Int. J. Parasitol. 37 (1): 11–20. doi:10.1016/j.ijpara.2006.09.009. PMID 17070814.
  30. ↑ McGowan K, Kane A, Asarkof N; et al. (1983). "Entamoeba histolytica causes intestinal secretion: role of serotonin". Science. 221 (4612): 762–4. doi:10.1126/science.6308760. PMID 6308760.
  31. ↑ McGowan K, Guerina V, Wicks J, Donowitz M (1985). "Secretory hormones of Entamoeba histolytica". Ciba Found. Symp. 112: 139–54. PMID 2861068.
  32. ↑ Park TJ, Comer C, Carol A, Lu Y, Hong HS, Rice FL (2003). "Somatosensory organization and behavior in naked mole-rats: II. Peripheral structures, innervation, and selective lack of neuropeptides associated with thermoregulation and pain". J Comp Neurol. 465 (1): 104–20. doi:10.1002/cne.10824. PMID 12926019.
  33. ↑ Pepling, Rachel Sheremeta (2004-01-07). "Ugly Ducklings". Chemical & Engineering News. Retrieved 2007-08-14.

External links

de:Substanz P it:Sostanza P nl:Substantie P fi:Substanssi P sv:Substans P

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