|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 otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is: / ?)(|
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its closely related 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. In 2014, the role of substance P to male aggression in fruit flies was identified.
The original discovery of Substance P (SP) was 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 been reported as well. 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. Subsequently, SP is 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 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. Also, SP can 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 and 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 called the Area Postrema, 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 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 used clinically 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 pain responses 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 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).
Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has been associated with many diseases: sickle cell crisis; inflammatory bowel disease; major depression and related disorders; fibromyalgia; rheumatological; and infections such as HIV/AIDS and respiratory syncytial virus, as well as in cancer.
When assayed in the intact human, the observed variability of the SP concentrations are large, and in some cases the assay methodology is questionable. SP concentrations cannot yet be used to diagnose disease clinically or gauge disease severity. It is not yet known whether changes in concentration of SP or density of its receptors is the cause of any given disease, or its effect.
As increasingly documented, the SP-NK1R system induces or modulates many aspects of the immune response, including WBC production and activation, and cytokine expression. Reciprocally, cytokines may induce expression of SP and its NK1R. In this sense, for diseases in which a pro-inflammatory component has been identified or strongly suspected, and for which current treatments are absent or in need of improvement, abrogation of the SP-NK1 system continues to receive focus as a treatment strategy. Currently, the only completely developed method available in that regard is antagonism (blockade, inhibition) of the SP preferring receptor, i.e., by drugs known as neurokinin type 1 antagonists (also termed: SP antagonists, or tachykinin antagonists.) One such drug is aprepitant to prevent the nausea and vomiting that accompanies chemotherapy, typically for cancer.
With the exception of chemotherapy-induced nausea and vomiting, the patho-physiological basis of many of the disease groups listed below, for which NK1RAs have been studied as a therapeutic intervention, are to varying extents hypothesized to be initiated or advanced by a chronic non-homeostatic inflammatory response.
Chemotherapy Induced Nausea and Vomiting
In line with its role as a first line defense system, SP is released when toxicants or poisons come into contact with a range of receptors on cellular elements in the chemoreceptor trigger zone, located in the floor of the fourth ventricle of the brain, the (area postrema). Presumably, SP is released in or around the Nucleus of the Solitary Tract upon integrated activity of dopamine, serotonin, opioid, and/or acetylcholine receptor signaling. NK1Rs are stimulated. In turn, a fairly complex reflex is triggered involving cranial nerves sub-serving respiration, retroperistalsis, and general autonomic discharge.
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 release of substance P into the synaptic cleft.
A suggestion of a link to male aggression was made in 2014. Confirmed in male fruit flies and discussed as a possibility in other species, even humans, who also have the gene that produces substance P, by neuroscientist David J. Anderson and others at California Institute of Technology researching "deep evolutionary roots of very fundamental behaviors". Clues found in the brains of fruit flies might lead to further research that reveals the role of substance P in similar behavior in those other species.
- Harrison S, Geppetti P (Jun 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 NA, Reece JB (2005). Biology (7th ed.). San Francisco: Pearson Benjamin Cummings. ISBN 9780805371468.
- Wong M, Jeng AY (Jan 1994). "Posttranslational modification of glycine-extended substance P by an alpha-amidating enzyme in cultured sensory neurons of dorsal root ganglia". Journal of Neuroscience Research 37 (1): 97–102. doi:10.1002/jnr.490370113. PMID 7511706.
- Gorman, James, To Study Aggression, a Fight Club for Flies, The New York Times, February 4, 2014, page D5 of the New York edition
- V Euler US, Gaddum JH (Jun 1931). "An unidentified depressor substance in certain tissue extracts". The Journal of Physiology 72 (1): 74–87. PMC 1403098. PMID 16994201.
- Pert CB (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 (Oct 1983). "Immunohistochemical localization of bombesin/gastrin-releasing peptide and substance P in primary sensory neurons". The Journal of Neuroscience 3 (10): 2021–9. PMID 6194276.
- Gerard NP, Garraway LA, Eddy RL, Shows TB, Iijima H, Paquet JL, Gerard C (Nov 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 (Sep 1995). "The mammalian tachykinin receptors". General Pharmacology 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 (Apr 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 (Apr 2007). "Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function". European 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 (Sep 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 (Nov 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 (Mar 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 (Oct 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 (Sep 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 (Sep 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 (Jul 2001). "Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting". Supportive Care in Cancer 9 (5): 350–4. doi:10.1007/s005200000199. PMID 11497388.
- Zubrzycka M, Janecka A (Dec 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 (Dec 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, Nimmo AJ, Cernak I, Blumbergs PC, Vink R (Aug 2009). "Substance P is associated with the development of brain edema and functional deficits after traumatic brain injury". Journal of Cerebral Blood Flow and Metabolism 29 (8): 1388–98. doi:10.1038/jcbfm.2009.63. PMID 19436311.
- Reid TW, Murphy CJ, Iwahashi CK, Foster BA, Mannis MJ (Aug 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 (Jul 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.
- Bossaller C, Reither K, Hehlert-Friedrich C, Auch-Schwelk W, Graf K, Gräfe M, Fleck E (Oct 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 (Nov 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.
- Michaels LA, Ohene-Frempong K, Zhao H, Douglas SD (Nov 1998). "Serum levels of substance P are elevated in patients with sickle cell disease and increase further during vaso-occlusive crisis". Blood 92 (9): 3148–51. PMID 9787150.
- Mantyh CR, Gates TS, Zimmerman RP, Welton ML, Passaro EP, Vigna SR, Maggio JE, Kruger L, Mantyh PW (May 1988). "Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn disease". Proceedings of the National Academy of Sciences of the United States of America 85 (9): 3235–9. doi:10.1073/pnas.85.9.3235. PMC 280179. PMID 2834738.
- Fehder WP, Sachs J, Uvaydova M, Douglas SD (1997). "Substance P as an immune modulator of anxiety". Neuroimmunomodulation 4 (1): 42–8. PMID 9326744.
- Geracioti TD, Carpenter LL, Owens MJ, Baker DG, Ekhator NN, Horn PS, Strawn JR, Sanacora G, Kinkead B, Price LH, Nemeroff CB (Apr 2006). "Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression". The American Journal of Psychiatry 163 (4). doi:10.1176/appi.ajp.163.4.637. PMID 16585438.
- Schwarz MJ, Ackenheil M (Mar 2002). "The role of substance P in depression: therapeutic implications". Dialogues in Clinical Neuroscience 4 (1). PMID 22033776.
- Rupniak NM (May 2002). "New insights into the antidepressant actions of substance P (NK1 receptor) antagonists". Canadian Journal of Physiology and Pharmacology 80 (5): 489–94. doi:10.1139/y02-048. PMID 12056558.
- Vaerøy H, Helle R, Førre O, Kåss E, Terenius L (Jan 1988). "Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis". Pain 32 (1). PMID 2448729.
- Anichini M, Cesaretti S, Lepori M, Maddali Bongi S, Maresca M, Zoppi M (Jan 1997). "Substance P in the serum of patients with rheumatoid arthritis". Revue Du Rhumatisme 64 (1): 18–21. PMID 9051855.
- Douglas SD, Ho WZ, Gettes DR, Cnaan A, Zhao H, Leserman J, Petitto JM, Golden RN, Evans DL (Oct 2001). "Elevated substance P levels in HIV-infected men". Aids 15 (15): 2043–5. doi:10.1097/00002030-200110190-00019. PMID 11600835.
- Palma C, Maggi CA (2000). "The role of tachykinins via NK1 receptors in progression of human gliomas". Life Sciences 67 (9): 985–1001. doi:10.1016/s0024-3205(00)00692-5. PMID 10954033.
- Singh D, Joshi DD, Hameed M, Qian J, Gascón P, Maloof PB, Mosenthal A, Rameshwar P (Jan 2000). "Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis". Proceedings of the National Academy of Sciences of the United States of America 97 (1): 388–93. doi:10.1073/pnas.97.1.388. PMC 26673. PMID 10618428.
- Campbell DE, Raftery N, Tustin R, Tustin NB, Desilvio ML, Cnaan A, Aye PP, Lackner AA, Douglas SD (Nov 2006). "Measurement of plasma-derived substance P: biological, methodological, and statistical considerations". Clinical and Vaccine Immunology 13 (11). doi:10.1128/CVI.00174-06. PMID 16971517.
- Ho WZ, Douglas SD (Dec 2004). "Substance P and neurokinin-1 receptor modulation of HIV". Journal of Neuroimmunology 157 (1-2). doi:10.1016/j.jneuroim.2004.08.022. PMID 15579279.
- Lambert N, Lescoulié PL, Yassine-Diab B, Enault G, Mazières B, De Préval C, Cantagrel A (Aug 1998). "Substance P enhances cytokine-induced vascular cell adhesion molecule-1 (VCAM-1) expression on cultured rheumatoid fibroblast-like synoviocytes". Clinical and Experimental Immunology 113 (2). PMID 9717978.
- Azzolina A, Bongiovanni A, Lampiasi N (Dec 2003). "Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cells". Biochimica Et Biophysica Acta 1643 (1-3). PMID 14654230.
- Douglas SD, Leeman SE (Jan 2011). "Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation". Annals of the New York Academy of Sciences 1217. doi:10.1111/j.1749-6632.2010.05826.x. PMID 21091716.
- Łazarczyk M, Matyja E, Lipkowski A. "Substance P and its receptors -- a potential target for novel medicines in malignant brain tumour therapies (mini-review)". Folia Neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences 45 (3). PMID 17849359.
- O'Connor TM, O'Connell J, O'Brien DI, Goode T, Bredin CP, Shanahan F (Nov 2004). "The role of substance P in inflammatory disease". Journal of Cellular Physiology 201 (2). doi:10.1002/jcp.20061. PMID 15334652.
- van der Hart MG (2009). Substance P and the Neurokinin 1 receptor: From behavior to bioanalysis (Ph.D.). University of Groningen. ISBN 978-90-367-3874-3.
- Hon KL, Lam MC, Wong KY, Leung TF, Ng PC (Nov 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 (Aug 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 (Jan 2007). "Irritable bowel syndrome: a review on the role of intestinal protozoa and the importance of their detection and diagnosis". International Journal for Parasitology 37 (1): 11–20. doi:10.1016/j.ijpara.2006.09.009. PMID 17070814.
- McGowan K, Kane A, Asarkof N, Wicks J, Guerina V, Kellum J, Baron S, Gintzler AR, Donowitz M (Aug 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). "Chapter 8: Secretory Hormones of Entamoeba histolytica". In D. Evered; J. Whelan. Microbial Toxins and Diarrhoeal Disease. Ciba Found. Symp. 112. pp. 139–54. doi:10.1002/9780470720936.ch8. PMID 2861068.
- Gorman, James, To Study Aggression, a Fight Club for Flies, The New York Times, February 4, 2014, page D5 of the New York edition
- Russell J (2001-09-14). "Neurochemical Substance P is Key to Understanding Pain Process". Fibromyalgia Library. ProHealth.com. Retrieved 2008-11-01.
- Fight Club for Flies video, Science Take, New York Times, February 3, 2014