Substance P

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Spacefilling model of substance P
tachykinin, precursor 1
Identifiers
Symbol TAC1
Alt. Symbols TAC2, NKNA
Entrez 6863
HUGO 11517
OMIM 162320
RefSeq NM_003182
UniProt P20366
Other data
Locus Chr. 7 q21-q22
Substance P
Identifiers
CAS number 33507-63-0
PubChem 36511
MeSH Substance+P
Properties
Molecular formula C63H98N18O13S
Molar mass 1347.63 g/mol
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox references

In the field of neuroscience, substance P is a neuropeptide: a short-chain polypeptide that functions as a neurotransmitter and as a neuromodulator which alters the excitability of the dorsal horn ganglion (pain responsive neurons).12 It belongs to the tachykinin neuropeptide family. Substance P is released from the terminals of specific sensory nerves. Substance P and its closely related neuropeptide neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. Subtance P is an 11-amino acid polypeptide with the following sequence:

  • Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met

Contents

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 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 region that are sensitive to cAMP, AP-1 and AP-4 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.10

Function

Substance P is one of the important complex mechanisms involved 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.11 SP has been associated in the regulation of mood disorders, anxiety, stress,12 reinforcement,13 neurogenesis,14 respiratory rhythm,15 neurotoxicity, nausea/emesis,16 pain and nociception.17 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.18 The regulated function of SP also involves the regulation of its high-affinity receptor, NK-1.Because of importance of substance P in perception of pain in animals, applying 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.19

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.11

Cellular growth

Substance P has been shown to stimulate cellular growth in cell culture,20 and it was shown that Substance P could promote wound healing of non-healing ulcers in humans.21 It has also been shown to reverse diabetes in mice.2223

Vasodilation

Substance P also has effects as a potent vasodilator. Substance P-induced vasodilatation is dependant on nitric oxide release.24 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).25

Clinical significance

Eczema

High levels of BDNF and Substance P have been found associated with increased itching in eczema.2627

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.2829 This protozoan was found to secrete serotonin30 as well as substance P and neurotensin.31

Deficiency

Naked mole rats lack Substance P and do not feel pain when painful stimuli are administered to the skin.3233 New studies have shown that when the function of SP is genetically disrupted in the mice, the animals demonstrated redcued responses to painful stimuli. Moreover, the response to capsaicin was absent or severely reduced in knockout mice.11

References

  1. ^ a b Harrison S, Geppetti P (June 2001). "Substance p". The International Journal of Biochemistry & Cell Biology 33 (6): 555–76. doi:10.1016/S1357-2725(01)00031-0. PMID 11378438. 
  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. PMID 14754378, http://www.bentham-direct.org/pages/content.php?CTMC/2004/00000004/00000001/0009R.SGM. 
  3. ^ V Euler US, Gaddum JH (June 1931). "An unidentified depressor substance in certain tissue extracts". The Journal of Physiology 72 (1): 74–87. PMID 16994201. PMC: 1403098, http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=16994201. 
  4. ^ Panula P, Hadjiconstantinou M, Yang HY, Costa E (October 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, http://www.jneurosci.org/cgi/content/abstract/3/10/2021. 
  5. ^ Gerard NP, Garraway LA, Eddy RL Jr, Shows TB, Iijima H, Paquet JL, Gerard C (November 1991). "Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones". Biochemistry 30 (44): 10640–6. PMID 1657150. 
  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 (May 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. PMID 7545030. PMC: 301212, http://www.molbiolcell.org/cgi/content/abstract/6/5/509. 
  8. ^ Yip J, Chahl LA (April 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. 
  9. ^ Gobbi G, Cassano T, Radja F, Morgese MG, Cuomo V, Santarelli L, Hen R, Blier P (April 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. 
  10. ^ Rameshwar P (November 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. 
  11. ^ a b c De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP (March 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. 
  12. ^ Ebner K, Singewald N (October 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. 
  13. ^ 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. PMID 7532865. 
  14. ^ Park SW, Yan YP, Satriotomo I, Vemuganti R, Dempsey RJ (September 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. 
  15. ^ Bonham AC (September 1995). "Neurotransmitters in the CNS control of breathing". Respiration physiology 101 (3): 219–30. doi:10.1016/0034-5687(95)00045-F. PMID 8606995. 
  16. ^ Hesketh PJ (July 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. 
  17. ^ Zubrzycka M, Janecka A (December 2000). "Substance P: transmitter of nociception (Minireview)". Endocrine regulations 34 (4): 195–201. PMID 11137976. 
  18. ^ 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. 
  19. ^ Hornby PJ (December 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. 
  20. ^ Reid TW, Murphy CJ, Iwahashi CK, Foster BA, Mannis MJ (August 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. 
  21. ^ Brown SM, Lamberts DW, Reid TW, Nishida T, Murphy CJ (July 1997). "Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike growth factor 1". Archives of Ophthalmology 115 (7): 926–7. PMID 9230840. 
  22. ^ Motluk A, Geddes L (2005-12-15). "Breakthrough sheds light on cause of diabetes". Health. New Scientist. Retrieved on 2008-11-01.
  23. ^ Tsui H, Razavi R, Chan Y, Yantha J, Dosch HM (October 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. 
  24. ^ Bossaller C, Reither K, Hehlert-Friedrich C, Auch-Schwelk W, Graf K, Gräfe M, Fleck E (October 1992). "In vivo measurement of endothelium-dependent vasodilation with substance P in man". Herz 17 (5): 284–90. PMID 1282120. 
  25. ^ Wong BJ, Tublitz NJ, Minson CT (November 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. PMID 16123103. 
  26. ^ Hon KL, Lam MC, Wong KY, Leung TF, Ng PC (November 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. 
  27. ^ Steinitz H (1979). "[Chronic recurrent intestinal amebiasis in Israel (author's transl)]" (in German). Leber, Magen, Darm 9 (4): 175–9. PMID 491812. 
  28. ^ 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. 
  29. ^ 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. 
  30. ^ McGowan K, Guerina V, Wicks J, Donowitz M (1985). "Secretory hormones of Entamoeba histolytica". Ciba Found. Symp. 112: 139–54. PMID 2861068. 
  31. ^ 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. 
  32. ^ Pepling, Rachel Sheremeta (2004-01-07). "Ugly Ducklings". Chemical & Engineering News. Retrieved on 2007-08-14.

External links

v • d • e
Pain and nociception
Head and neck
Thorax
Abdominal
Limbs
Joints (arthralgia)
Musculoskeletal
Other/unspecified
Related concepts
v • d • e
Kinins, neuropeptides: tachykinins
Mammal
Substance P - Neurokinin A - Neurokinin B
Amphibian

Wikipedia content modification information:

  • This page was last modified on 11 November 2008, at 21:11.

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