Substance P

tachykinin, precursor 1

Spacefilling model of substance P
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
33507-63-0 Yes
ChEMBL ChEMBL235363 Yes
ChemSpider 33558 Yes
MeSH Substance+P
PubChem 36511
UNII 675VGV5J1D 
Properties
C63H98N18O13S
Molar mass 1347.63 g/mol
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
  verify (what is: Yes/?)
Infobox references

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.[1][2] 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:[3]

with an amidation at the C-terminus.[4] 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 (SP) was originally discovered in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro.[5] Its tissue distribution and biologic actions were further investigated over the following decades.[1] The eleven-amino-acid structure of the peptide was determined by Susan Leeman in 1971.[6]

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.[7]

Receptor

The endogenous receptor for substance P is neurokinin 1 receptor (NK1-receptor, NK1R).[8] It belongs to the tachykinin receptor sub-family of GPCRs.[9] 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.[10] 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).[11] They are also found in close association with serotonin (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs.[12] The SP receptor promoter contains regions that are sensitive to cAMP, AP-1, AP-4, CEBPB,[13] 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.[14]

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.[15] Substance P has been associated with the regulation of mood disorders, anxiety, stress,[16] reinforcement,[17] neurogenesis,[18] respiratory rhythm,[19] neurotoxicity, nausea/emesis,[20] pain and nociception.[21] 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.[22] 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 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.[23] 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, 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.[15]

Substance P increases glutamate activity (NMDA) in central nervous system, and it is associated with the development of brain edema and functional deficits after traumatic brain injury.[24]

Cell growth

Substance P has been known to stimulate cell growth in culture,[25] and it was shown that substance P could promote wound healing of non-healing ulcers in humans.[26]

Diabetes

Substance P injected into pancreatic nerves has been shown to reverse diabetes in mice[27][28] 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.[29]

Vasodilation

Substance P also has effects as a potent vasodilator. Substance P-induced vasodilatation is dependent on nitric oxide release.[30] 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).[31] 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

Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has been associated with many diseases: sickle cell crisis;[32] inflammatory bowel disease;[33][34] major depression and related disorders;[35][36][37] fibromyalgia;[38] rheumatological;[39] and infections such as HIV/AIDS and respiratory syncytial virus,[40] as well as in cancer.[41][42]

When assayed in the intact human, the observed variability of the SP concentrations are large, and in some cases the assay methodology is questionable.[43] SP concentrations cannot yet be used to clinically diagnose disease 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.[44] Reciprocally, cytokines may induce expression of SP and its NK1R.[45][46] 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 which accompanies chemotherapy, typically of 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.[47][48][49][50][51]

Chemotherapy Induced Nausea and Vomiting

see: Chemotherapy-induced nausea and vomiting and Aprepitant

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.

Inflammatory Skin Diseases

Eczema

High levels of BDNF and substance P have been found associated with increased itching in eczema.[52][53]

Infections

Entamoeba Histolytica

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.[54][55] This protozoan was found to secrete serotonin[56] as well as substance P and neurotensin.[57]

Other

Denervation supersensitivity

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.

Deficiency

Naked mole-rats (Heterocephalus glaber, NMR) 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.[58][59] 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.[15]

Two other features of the NMR are compelling: 1) with a lifespan up to 28 years, it is the longest living of all rodents, and 2) it has marked resistance to cancer.[60] Although NK1Rs are intact in the NMR, it is unclear whether SP is diminished system-wide or just in skin. This is a potentially important question for future studies on the mechanisms underlying the NMR's resistance to cancer beyond contact inhibition via p53 and pRb tumor suppressor pathways in the animal. Abundant preclinical data now support a potentially significant role of SP in promoting mitogenesis, cell motility and neoangiogenesis. NK1 antagonism has been commended as a potential anticancer mechanism by several groups independent groups.[61]

References

  1. ↑ 1.0 1.1 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.
  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. ↑ Campbell NA, Reece JB (2005). Biology (7th ed.). San Francisco: Pearson Benjamin Cummings. ISBN 9780805371468.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ Pert CB (2012). Molecules Of Emotion: Why You Feel The Way You Feel. Simon and Schuster. ISBN 1471109704. Retrieved 31 July 2014.
  7. ↑ 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.
  8. ↑ Gerard NP, Garraway LA, Eddy RL, Shows TB, Iijima H, Paquet JL et al. (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.
  9. ↑ Maggi CA (Sep 1995). "The mammalian tachykinin receptors". General Pharmacology 26 (5): 911–44. doi:10.1016/0306-3623(94)00292-U. PMID 7557266.
  10. ↑ 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.
  11. ↑ 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.
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