|tachykinin, precursor 1|
Spacefilling model of substance P
|Alt. symbols||TAC2, NKNA|
|Locus||Chr. 7 q21-q22|
|Molar mass||1347.63 g/mol|
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
|(what is: / ?)|
In the field of neuroscience, substance P (SP) is a neuropeptide - a substance that functions as a neurotransmitter and as a neuromodulator. To be specific, substance P is an undecapeptide - a peptide composed of a chain of 11 amino acid residues. 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:
with an amidation at the C-terminus. 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.
Substance P (SP) was originally discovered in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro. Its tissue distribution and biologic actions were further investigated over the following decades. The eleven-amino-acid structure of the peptide was determined by Susan Leeman in 1971.
The endogenous receptor for substance P is neurokinin 1 receptor (NK1-receptor, NK1R). It belongs to the tachykinin receptor sub-family of GPCRs. 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-dependent mechanism to the acidified endosomes where the complex disassociates. SP is subsequently degraded and NK-1 is re-expressed on the cell surface. Substance P and the NK1 receptor are widely distributed in the brain and are found in brain regions that are specific to regulating emotion (hypothalamus, amygdala, and the periaqueductal gray). They are also found in close association with serotonin (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs. The SP receptor promoter contains regions that are sensitive to cAMP, AP-1, AP-4, CEBPB, 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.
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. Substance P has been associated with the regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm, neurotoxicity, nausea/emesis, pain and nociception. 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. 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.
The vomiting center in the medulla 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. Substance P antagonist (SPA) aprepitant is available in the market in the treatment of chemotherapy-induced nausea/emesis.
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, it is presumed, 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 an anti-inflammatory agent to reduce 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 K2 and K3 agonists. Based on recent studies, it was proposed that NK1, and possibly 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.
Substance P injected into pancreatic nerves has been shown to reverse diabetes in mice but effects to insulin secretion seem to be species-dependent. In humans, substance P given intravenously seems to decrease insulin release and causes fluctuations in blood sugar levels.
Substance P also has effects as a potent vasodilator. Substance P-induced vasodilatation is dependent on nitric oxide release. 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 suggests an internalization of neurokinin-1 (NK1). 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).
Entamoeba histolytica is a unicellular parasitic protozoan that infects the lower gastrointestinal tract of humans. The symptoms of infection are diarrhea, constipation, and abdominal pain. This protozoan was found to secrete serotonin as well as substance P and neurotensin.
When the innervation to substance P nerve terminals is lost, post-synaptic cells compensate for the loss of adequate neurotransmitter by increasing the expression of post-synaptic receptors. This, ultimately, leads to a condition known as Denervation Supersensitivity as the post-synaptic nerves will become hypersensitive to any invasion of substance P into the synaptic cleft.
Naked mole rats lack cutaneous C fibers reactive to substance P (SP) and many small neurons that are normally SP-positive. Thus, these animals are insensitive to pain when painful stimuli are administered to the skin. 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.
- 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.
- 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.
- Campbell, Neil A, and Jane B Reece. Biology. 7th ed. San Francisco: Pearson Education, Inc., n.d.Print.
- Wong M, Jeng AY (1994). "Posttranslational modification of glycine-extended substance P by an alpha-amidating enzyme in cultured sensory neurons of dorsal root ganglia.". J Neurosci Res 37 (1): 97–102. doi:10.1002/jnr.490370113. PMID 7511706.
- V Euler US, Gaddum JH (June 1931). "An unidentified depressor substance in certain tissue extracts". The Journal of Physiology 72 (1): 74–87. PMC 1403098. PMID 16994201.
- Candace B. Pert (2012). "Molecules Of Emotion: Why You Feel The Way You Feel". Simon and Schuster. ISBN 1471109704. Retrieved 31 July 2014.
- Panula P, Hadjiconstantinou M, Yang HY, Costa E (October 1983). "Immunohistochemical localization of bombesin/gastrin-releasing peptide and substance P in primary sensory neurons". Journal of Neuroscience 3 (10): 2021–9. PMID 6194276.
- 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. doi:10.1021/bi00108a006. PMID 1657150.
- Maggi CA (1995). "The mammalian tachykinin receptors". Gen. Pharmacol. 26 (5): 911–44. doi:10.1016/0306-3623(94)00292-U. PMID 7557266.
- 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. doi:10.1091/mbc.6.5.509. PMC 301212. PMID 7545030.
- 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.
- 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.
- Kovács KA, Steinmann M, Magistretti PJ, Halfon O, Cardinaux JR (September 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Zubrzycka M, Janecka A (December 2000). "Substance P: transmitter of nociception (Minireview)". Endocrine regulations 34 (4): 195–201. PMID 11137976.
- 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.
- Hornby PJ (December 2001). "Central neurocircuitry associated with emesis". The American Journal of Medicine. 111. Suppl 8A (8): 106S–112S. doi:10.1016/S0002-9343(01)00849-X. PMID 11749934.
- Donkin JJ, lNimmo AJ, Cernak I, Blumbergs PC, Vink R (August 2009). "Substance P is associated with the development of brain edema and functional deficits after traumatic brain injury". J Cereb Blood Flow Metab. 29 (8): 1388–98. doi:10.1038/jcbfm.2009.63. PMID 19436311.
- 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.
- 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. doi:10.1001/archopht.1997.01100160096021. PMID 9230840.
- Motluk A, Geddes L (2005-12-15). "Breakthrough sheds light on cause of diabetes". Health. New Scientist. Retrieved 2008-11-01.
- 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.
- Brown, M and Vale, W (1976). "Effects of neurotensin and substance P on plasma insulin, glucagon and glucose levels". Endocrinology 98 (3): 819–822. doi:10.1210/endo-98-3-819. PMID 1261503.
- 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.
- 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. PMC 1464169. PMID 16123103.
- 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.
- Steinitz H (1979). "[Chronic recurrent intestinal amebiasis in Israel (author's transl)]". Leber, Magen, Darm (in German) 9 (4): 175–9. PMID 491812.
- 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.
- 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.
- McGowan K, Guerina V, Wicks J, Donowitz M (1985). "Secretory hormones of Entamoeba histolytica". Ciba Found. Symp. 112: 139–54. doi:10.1002/9780470720936.ch8. PMID 2861068.
- 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.
- Pepling, Rachel Sheremeta (2004-01-07). "Ugly Ducklings". Chemical & Engineering News. Retrieved 2007-08-14.
- Russell J (2001-09-14). "Neurochemical Substance P is Key to Understanding Pain Process". Fibromyalgia Library. ProHealth.com. Retrieved 2008-11-01.