TRPA1

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Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1 or TRPA1, is a protein that in humans is encoded by the TRPA1 (and in other species by the Trpa1) gene.[1][2]

TRPA1 is an ion channel located on the plasma membrane of many human and animal cells. This ion channel is best known as a sensor for environmental irritants giving rise to somatosensory modalities such as pain, cold and itch.[3][4]

Function

TRPA1 is a member of the transient receptor potential channel family.[2] TRPA1 contains 14 N-terminal ankyrin repeats and is believed to function as a mechanical and chemical stress sensor.[5] The specific function of this protein has not yet been determined; however, studies indicate that the function may involve a role in signal transduction and growth control.[6]

Recent studies indicate that TRPA1 is activated by a number of reactive [3][4][7] (allyl isothiocyanate, cinnamaldehyde, farnesyl thiosalicylic acid, formalin, hydrogen peroxide, 4-hydroxynonenal, acrolein, and tear gases[8]) and non-reactive compounds (nicotine,[9] PF-4840154[10]) and considered as a "chemosensor" in the body.[11]. TRPA1 is co-expressed with TRPV1 on nociceptive primary afferent C-fibers in humans.[12] This sub-population of peripheral C-fibers is considered important sensors of nociception in humans and their activation will under normal conditions give rise to pain.[13] Indeed, TRPA1 is considered as an attractive pain target based on the fact that TRPA1 knockout mice showed near complete attenuation of formalin-induced pain behaviors.[14][15] TRPA1 antagonists are effective in blocking pain behaviors induced by inflammation (complete Freund's adjuvant and formalin).

Although it is not firmly confirmed whether noxious cold sensation is mediated by TRPA1 in vivo, several recent studies clearly demonstrated cold activation of TRPA1 channels in vitro.[16][17]

In the heat-sensitive loreal pit organs of many snakes TRPA1 is responsible for the detection of infrared radiation.[18]

Clinical significance

In 2008, it was observed that caffeine suppresses activity of human TRPA1, but it was found that mouse TRPA1 channels expressed in sensory neurons cause an aversion to drinking caffeine-containing water, suggesting that the TRPA1 channels mediate the perception of caffeine.[19]

TRPA1 has also been implicated in causing the skin irritation experienced by some smokers trying to quit by using nicotine replacement therapies such as inhalers, sprays, or patches.[9] A missense mutation of TRPA1 was found to be the cause of a hereditary episodic pain syndrome. A family from Colombia suffers from "debilitating upper-body pain starting in infancy" that is "usually triggered by fasting or fatigue (illness, cold temperature, and physical exertion being contributory factors)". A gain-of-function mutation in the fourth transmembrane domain causes the channel to be overly sensitive to pharmacological activation.[20]

Metabolites of paracetamol (acetaminophen) have been demonstrated to bind to the TRPA1 receptors (probably agonism which then can lead to desensitization of TRPA1 receptors in the way that capsaicin does it in the spinal cord of mice, causing an antinociceptive effect. This is suggested as the antinociceptive mechanism for paracetamol.[21]

Oxalate, a metabolite of an anti cancer drug oxaliplatin, has been demonstrated to inhibit prolyl hydroxylase, which endows cold-insensitive human TRPA1 with pseudo cold sensitivity (via reactive oxygen generation from mitochondria). This may cause a characteristic side-effect of oxaliplatin (cold-triggered acute peripheral neuropathy).[22]

Ligand binding

TRPA1 can be considered to be one of the most promiscuous TRP ion channels, as it seems to be activated by a large number of noxious chemicals found in many plants, food, cosmetics and pollutants.[23]

Activation of the TRPA1 ion channel by the olive oil phenolic compound oleocanthal appears to be responsible for the pungent or "peppery" sensation in the back of the throat caused by olive oil.[24][25]

Although several nonelectrophilic agents such as thymol and menthol have been reported as TRPA1 agonists, most of the known activators are electrophilic chemicals that have been shown to activate the TRPA1 receptor via the formation of a reversible covalent bond with cysteine residues present in the ion channel.[26][27] For a broad range of electrophilic agents, chemical reactivity in combination with a lipophilicity enabling membrane permeation is crucial to TRPA1 agonistic effect. A dibenz[b,f][1,4]oxazepine derivative substituted by a carboxylic methylester at position 10 is the most potent TRPA1 agonist discovered to date (EC50 = 50 pM).[28] The pyrimidine PF-4840154 is a potent, non-covalent activator of both the human (EC50 = 23 nM) and rat (EC50 = 97 nM) TrpA1 channels. This compound elicits nociception in a mouse model through TrpA1 activation. Furthermore, PF-4840154 is superior to allyl isothiocyanate, the pungent component of mustard oil, for screening purposes.[10]

The eicosanoids formed in the ALOX12 (i.e. arachidonate-12-lipoxygnease) pathway of arachidonic acid metabolism, 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (i.e. 12S-HpETE; see 12-Hydroxyeicosatetraenoic acid) and the hepoxilins (Hx), HxA3 (i.e. 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and HxB3 (i.e. 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid) (see Hepoxilin#Pain perception) directly activate TRPA1 and thereby contribute to the hyperalgesia and tactile allodynia responses of mice to skin inflammation. In this animal model of pain perception, the hepoxilins are released in spinal cord and directly activate TRPA (and also TRPV1) receptors to augment the perception of pain.[29][30][31][32] 12S-HpETE, which is the direct precursor to HxA3 and HxB3 in the ALOX12 pathway, may act only after being converted to these hepoxilins.[31] The epoxide, 4,5-epoxy-8Z,11Z,14Z-eicosatrienoic acid (4,5-EET) made by the metabolism of arachidonic acid by any one of several cytochrome P450 enzymes (see Epoxyeicosatrienoic acid) likewise directly activates TRPA1 to amplify pain perception.[31]

Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that another arachidonic acid metabolite, Prostaglandin E2, operates through its prostaglandin EP3 G protein coupled receptor to trigger cough responses. Its mechanism of action does not appear to involve direct binding to TRPA1 but rather the indirect activation and/or sensitization of TRPA1 as well as TRPV1 receptors. Genetic polymorphism in the EP3 receptor (rs11209716[33]), has been associated with ACE inhibitor-induce cough in humans.[34][35]

TRPA1 inhibition

Resolvin D1 (RvD1) and RvD2 (see resolvins) and maresin 1 are metabolites of the omega 3 fatty acid, docosahexaenoic acid. They are members of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, in humans. These SPMs also damp pain perception arising from various inflammation-based causes in animal models. The mechanism behind their pain-dampening effect involves the inhibition of TRPA1, probably (in at least certain cases) by an indirect effect wherein they activate another receptor located on neurons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which SPMs may operate to down-regulate TRPs and thereby pain perception.[36][37][38][39][40]

Ligand examples

Agonists

Antagonists

  • HC030031
  • GRC17536
  • A-967079
  • ALGX-2513
  • ALGX-2541
  • ALGX-2563
  • ALGX-2561
  • ALGX-2542

References

  1. ↑ Jaquemar D, Schenker T, Trueb B (Mar 1999). "An ankyrin-like protein with transmembrane domains is specifically lost after oncogenic transformation of human fibroblasts". The Journal of Biological Chemistry. 274 (11): 7325–33. doi:10.1074/jbc.274.11.7325. PMID 10066796.
  2. ↑ 2.0 2.1 Clapham DE, Julius D, Montell C, Schultz G (Dec 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological Reviews. 57 (4): 427–50. doi:10.1124/pr.57.4.6. PMID 16382100.
  3. ↑ 3.0 3.1 Andersen HH, Elberling J, Arendt-Nielsen L (May 2015). "Human Surrogate Models of Histaminergic and Non-histaminergic Itch". Acta Dermato-Venereologica. 95 (7): 771–7. doi:10.2340/00015555-2146. PMID 26015312.
  4. ↑ 4.0 4.1 Højland CR, Andersen HH, Poulsen JN, Arendt-Nielsen L, Gazerani P (Mar 2015). "A Human Surrogate Model of Itch Utilizing the TRPA1 Agonist Trans-cinnamaldehyde" (PDF). Acta Dermato-Venereologica. 95 (7): 798–803. doi:10.2340/00015555-2103. PMID 25792226.
  5. ↑ García-Añoveros J, Nagata K (2007). "TRPA1". Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology. 179. pp. 347–62. doi:10.1007/978-3-540-34891-7_21. ISBN 978-3-540-34889-4. PMID 17217068.
  6. ↑ "Entrez Gene: TRPA1 transient receptor potential cation channel, subfamily A, member 1".
  7. ↑ Baraldi PG, Preti D, Materazzi S, Geppetti P (Jul 2010). "Transient receptor potential ankyrin 1 (TRPA1) channel as emerging target for novel analgesics and anti-inflammatory agents". Journal of Medicinal Chemistry. 53 (14): 5085–107. doi:10.1021/jm100062h. PMID 20356305.
  8. ↑ Brône B, Peeters PJ, Marrannes R, Mercken M, Nuydens R, Meert T, Gijsen HJ (Sep 2008). "Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor". Toxicology and Applied Pharmacology. 231 (2): 150–6. doi:10.1016/j.taap.2008.04.005. PMID 18501939.
  9. ↑ 9.0 9.1 Talavera K, Gees M, Karashima Y, Meseguer VM, Vanoirbeek JA, Damann N, Everaerts W, Benoit M, Janssens A, Vennekens R, Viana F, Nemery B, Nilius B, Voets T (Oct 2009). "Nicotine activates the chemosensory cation channel TRPA1". Nature Neuroscience. 12 (10): 1293–9. doi:10.1038/nn.2379. hdl:10261/16906. PMID 19749751.
  10. ↑ 10.0 10.1 Ryckmans T, Aubdool AA, Bodkin JV, Cox P, Brain SD, Dupont T, Fairman E, Hashizume Y, Ishii N, Kato T, Kitching L, Newman J, Omoto K, Rawson D, Strover J (Aug 2011). "Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel". Bioorganic & Medicinal Chemistry Letters. 21 (16): 4857–9. doi:10.1016/j.bmcl.2011.06.035. PMID 21741838.
  11. ↑ Tai C, Zhu S, Zhou N (Jan 2008). "TRPA1: the central molecule for chemical sensing in pain pathway?". The Journal of Neuroscience. 28 (5): 1019–21. doi:10.1523/JNEUROSCI.5237-07.2008. PMID 18234879.
  12. ↑ Nielsen TA, Eriksen MA, Gazerani P, Andersen HH (Aug 2018). "Psychophysical and vasomotor evidence for interdependency of TRPA1 and TRPV1-evoked nociceptive responses in human skin: an experimental study". Pain. 159 (10): 1989–2001. doi:10.1097/j.pain.0000000000001298. PMID 29847470.
  13. ↑ Andersen HH, Lo Vecchio S, Gazerani P, Arendt-Nielsen L (Jul 2017). "Dose–response study of topical allyl isothiocyanate (mustard oil) as a human surrogate model of pain, hyperalgesia, and neurogenic inflammation". Pain. 158 (9): 1723–32. doi:10.1097/j.pain.0000000000000979. PMID 28614189.
  14. ↑ McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM, Fanger CM (Aug 2007). "TRPA1 mediates formalin-induced pain". Proceedings of the National Academy of Sciences of the United States of America. 104 (33): 13525–30. doi:10.1073/pnas.0705924104. PMC 1941642. PMID 17686976.
  15. ↑ McMahon SB, Wood JN (Mar 2006). "Increasingly irritable and close to tears: TRPA1 in inflammatory pain". Cell. 124 (6): 1123–5. doi:10.1016/j.cell.2006.03.006. PMID 16564004.
  16. ↑ Sawada Y, Hosokawa H, Hori A, Matsumura K, Kobayashi S (Jul 2007). "Cold sensitivity of recombinant TRPA1 channels". Brain Research. 1160: 39–46. doi:10.1016/j.brainres.2007.05.047. PMID 17588549.
  17. ↑ Klionsky L, Tamir R, Gao B, Wang W, Immke DC, Nishimura N, Gavva NR (2007). "Species-specific pharmacology of Trichloro(sulfanyl)ethyl benzamides as transient receptor potential ankyrin 1 (TRPA1) antagonists". Molecular Pain. 3: 1744–8069–3–39. doi:10.1186/1744-8069-3-39. PMC 2222611. PMID 18086308.
  18. ↑ Gracheva EO, Ingolia NT, Kelly YM, Cordero-Morales JF, Hollopeter G, Chesler AT, Sánchez EE, Perez JC, Weissman JS, Julius D (Apr 2010). "Molecular basis of infrared detection by snakes". Nature. 464 (7291): 1006–11. doi:10.1038/nature08943. PMC 2855400. PMID 20228791.
  19. ↑ Nagatomo K, Kubo Y (Nov 2008). "Caffeine activates mouse TRPA1 channels but suppresses human TRPA1 channels". Proceedings of the National Academy of Sciences of the United States of America. 105 (45): 17373–8. doi:10.1073/pnas.0809769105. PMC 2582301. PMID 18988737.
  20. ↑ Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, Marsh S, Woods CG, Jones NG, Paterson KJ, Fricker FR, Villegas A, Acosta N, Pineda-Trujillo NG, Ramírez JD, Zea J, Burley MW, Bedoya G, Bennett DL, Wood JN, Ruiz-Linares A (Jun 2010). "A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome". Neuron. 66 (5): 671–80. doi:10.1016/j.neuron.2010.04.030. PMC 4769261. PMID 20547126.
  21. ↑ Andersson DA, Gentry C, Alenmyr L, Killander D, Lewis SE, Andersson A, Bucher B, Galzi JL, Sterner O, Bevan S, Högestätt ED, Zygmunt PM (2011-11-22). "TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ(9)-tetrahydrocannabiorcol". Nature Communications. 2 (2): 551. doi:10.1038/ncomms1559. PMID 22109525.
  22. ↑ Miyake T, Nakamura S, Zhao M, So K, Inoue K, Numata S, Takahashi N, Shirakawa H, Mori Y, Nakagawa T, Kaneko S (2016-09-15). "Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS". Nature Communications. 7: 12840. doi:10.1038/ncomms12840. PMC 5027619. PMID 27628562.
  23. ↑ Boonen, Brett; Startek, Justyna B.; Talavera, Karel (2016-01-01). Taste and Smell. Topics in Medicinal Chemistry. 23. Springer Berlin Heidelberg. pp. 1–41. doi:10.1007/7355_2015_98. ISBN 978-3-319-48925-4.
  24. ↑ Peyrot des Gachons C, Uchida K, Bryant B, Shima A, Sperry JB, Dankulich-Nagrudny L, Tominaga M, Smith AB, Beauchamp GK, Breslin PA (Jan 2011). "Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal". The Journal of Neuroscience. 31 (3): 999–1009. doi:10.1523/JNEUROSCI.1374-10.2011. PMC 3073417. PMID 21248124.
  25. ↑ Cicerale S, Breslin PA, Beauchamp GK, Keast RS (May 2009). "Sensory characterization of the irritant properties of oleocanthal, a natural anti-inflammatory agent in extra virgin olive oils". Chemical Senses. 34 (4): 333–9. doi:10.1093/chemse/bjp006. PMC 4357805. PMID 19273462.
  26. ↑ Hinman A, Chuang HH, Bautista DM, Julius D (Dec 2006). "TRP channel activation by reversible covalent modification". Proceedings of the National Academy of Sciences of the United States of America. 103 (51): 19564–8. doi:10.1073/pnas.0609598103. PMC 1748265. PMID 17164327.
  27. ↑ Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG, Cravatt BF, Patapoutian A (Feb 2007). "Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines". Nature. 445 (7127): 541–5. doi:10.1038/nature05544. PMID 17237762.
  28. ↑ Gijsen HJ, Berthelot D, Zaja M, Brône B, Geuens I, Mercken M (Oct 2010). "Analogues of morphanthridine and the tear gas dibenz[b,f][1,4]oxazepine (CR) as extremely potent activators of the human transient receptor potential ankyrin 1 (TRPA1) channel". Journal of Medicinal Chemistry. 53 (19): 7011–20. doi:10.1021/jm100477n. PMID 20806939.
  29. ↑ Gregus AM, Doolen S, Dumlao DS, Buczynski MW, Takasusuki T, Fitzsimmons BL, Hua XY, Taylor BK, Dennis EA, Yaksh TL (April 2012). "Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors". Proceedings of the National Academy of Sciences of the United States of America. 109 (17): 6721–6. doi:10.1073/pnas.1110460109. PMC 3340022. PMID 22493235.
  30. ↑ Gregus AM, Dumlao DS, Wei SC, Norris PC, Catella LC, Meyerstein FG, Buczynski MW, Steinauer JJ, Fitzsimmons BL, Yaksh TL, Dennis EA (May 2013). "Systematic analysis of rat 12/15-lipoxygenase enzymes reveals critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia". FASEB Journal. 27 (5): 1939–49. doi:10.1096/fj.12-217414. PMC 3633813. PMID 23382512.
  31. ↑ 31.0 31.1 31.2 Koivisto A, Chapman H, Jalava N, Korjamo T, Saarnilehto M, Lindstedt K, Pertovaara A (January 2014). "TRPA1: a transducer and amplifier of pain and inflammation". Basic & Clinical Pharmacology & Toxicology. 114 (1): 50–5. doi:10.1111/bcpt.12138. PMID 24102997.
  32. ↑ Pace-Asciak CR (April 2015). "Pathophysiology of the hepoxilins". Biochimica et Biophysica Acta. 1851 (4): 383–96. doi:10.1016/j.bbalip.2014.09.007. PMID 25240838.
  33. ↑ "Reference SNP (refSNP) Cluster Report: Rs11209716".
  34. ↑ Maher SA, Dubuis ED, Belvisi MG (2011). "G-protein coupled receptors regulating cough". Current Opinion in Pharmacology. 11 (3): 248–53. doi:10.1016/j.coph.2011.06.005. PMID 21727026.
  35. ↑ Grilo A, Sáez-Rosas MP, Santos-Morano J, Sánchez E, Moreno-Rey C, Real LM, Ramírez-Lorca R, Sáez ME (2011). "Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough". Pharmacogenetics and Genomics. 21 (1): 10–7. doi:10.1097/FPC.0b013e328341041c. PMID 21052031.
  36. ↑ Qu Q, Xuan W, Fan GH (2015). "Roles of resolvins in the resolution of acute inflammation". Cell Biology International. 39 (1): 3–22. doi:10.1002/cbin.10345. PMID 25052386.
  37. ↑ Serhan CN, Chiang N, Dalli J, Levy BD (2015). "Lipid mediators in the resolution of inflammation". Cold Spring Harbor Perspectives in Biology. 7 (2): a016311. doi:10.1101/cshperspect.a016311. PMC 4315926. PMID 25359497.
  38. ↑ Lim JY, Park CK, Hwang SW (2015). "Biological Roles of Resolvins and Related Substances in the Resolution of Pain". BioMed Research International. 2015: 1–14. doi:10.1155/2015/830930. PMC 4538417. PMID 26339646.
  39. ↑ Ji RR, Xu ZZ, Strichartz G, Serhan CN (2011). "Emerging roles of resolvins in the resolution of inflammation and pain". Trends in Neurosciences. 34 (11): 599–609. doi:10.1016/j.tins.2011.08.005. PMC 3200462. PMID 21963090.
  40. ↑ Serhan CN, Chiang N, Dalli J (2015). "The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution". Seminars in Immunology. 27 (3): 200–15. doi:10.1016/j.smim.2015.03.004. PMC 4515371. PMID 25857211.
  41. ↑ MacPherson, Lindsey J.; Dubin, Adrienne E.; Evans, Michael J.; Marr, Felix; Schultz, Peter G.; Cravatt, Benjamin F.; Patapoutian, Ardem (2007). "Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines". Nature. 445 (7127): 541–545. doi:10.1038/nature05544. PMID 17237762.

External links

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