substance P

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 (SP) is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator which alters the excitability of the dorsal horn ganglion (pain responsive neurons).^[1][2] 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. The deduced amino acid sequence of substance P is as follows:

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

It is a protein found in the brain and spinal cord, and is associated with some inflammatory processes in the joints.^{[citation needed]} Its function is to cause pain, particularly in arthritis, low back pain and fibromyalgia.^{[citation needed]} Release of substance P has also been associated with migraine headaches.

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 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 known 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.^[22][23]

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] 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.^[26][27]

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.^[28][29] This protozoan was found to secrete serotonin^[30] 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.^[32][33] New studies have shown that when the function of SP is genetically disrupted in the mice, the animals demonstrated reduced responses to painful stimuli. Moreover, the response to capsaicin was absent or severely reduced in knockout mice.^[11]

References

External links

• Russell J (2001-09-14). "Neurochemical Substance P is Key to Understanding Pain Process". Fibromyalgia Library. ProHealth.com. http://www.fibromyalgiasupport.com/library/showarticle.cfm/id/3097. Retrieved on 2008-11-01.