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TRPA1

TRPA1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTRPA1, ANKTM1, FEPS, transient receptor potential cation channel subfamily A member 1, FEPS1
External IDsOMIM: 604775; MGI: 3522699; HomoloGene: 7189; GeneCards: TRPA1; OMA:TRPA1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8989

277328

Ensembl

ENSG00000104321

ENSMUSG00000032769

UniProt

O75762

Q8BLA8

RefSeq (mRNA)

NM_007332

NM_177781
NM_001348288

RefSeq (protein)

NP_015628

NP_808449
NP_001335217

Location (UCSC)Chr 8: 72.02 – 72.08 MbChr 1: 14.94 – 14.99 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Mustard and Wasabi Receptor, is a protein that in humans is encoded by the TRPA1 (and in mice and rats by the Trpa1) gene.[5][6]

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 pain, cold and itch in humans and other mammals, as well as a sensor for environmental irritants giving rise to other protective responses (tears, airway resistance, and cough).[7][8]

Function

TRPA1 is a member of the transient receptor potential channel family.[6] TRPA1 contains 14 N-terminal ankyrin repeats and is believed to function as a mechanical and chemical stress sensor.[9] One of the specific functions of this protein studies involves a role in the detection, integration and initiation of pain signals in the peripheral nervous system.[10] It can be activated at sites of tissue injury or sites of inflammation directly by endogenous mediators or indirectly as a downstream target via signaling from a number of distinct G-protein coupled receptors (GPCRs), such as bradykinin.

The role of TRPA1 in pain sensing was first revealed when TRPA1 was identified as the receptor for mustard oil (allyl isothiocyanate), the pungent ingredient in mustard and wasabi.[7] Recent studies indicate that TRPA1 is activated by a number of reactive [8][11] (cinnamaldehyde, farnesyl thiosalicylic acid, formalin, hydrogen peroxide, 4-hydroxynonenal, acrolein, and tear gases[12][13][14]) and non-reactive compounds (nicotine,[15] PF-4840154[16]) and is thus considered as a "chemosensor" in the body.[17] TRPA1 is co-expressed with TRPV1 on nociceptive primary afferent C-fibers in humans.[18] 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.[19] Indeed, TRPA1 is considered as an attractive pain target. TRPA1 knockout mice showed near complete attenuation of nocifensive behaviors to formalin, tear-gas and other reactive chemicals .[20][21] TRPA1 antagonists are effective in blocking pain behaviors induced by inflammation (complete Freund's adjuvant and formalin).

Although it is not fully confirmed whether noxious cold sensation is mediated by TRPA1 in vivo, several recent studies clearly demonstrated cold activation of TRPA1 channels in vitro.[22][23]

In the heat-sensitive loreal pit organs of many snakes, TRPA1 is responsible for the detection of infrared radiation.[24][25]

Structure

In 2016, cryo-electron microscopy was employed to obtain a three-dimensional structure of TRPA1. This work revealed that the channel assembles as a homotetramer, and possesses several structural features that hint at its complex regulation by irritants, cytoplasmic second messengers (e.g., calcium), cellular co-factors (e.g., inorganic anions like polyphosphates), and lipids (e.g., PIP2). Most notably, the site of covalent modification and activation for electrophilic irritants was localized to a tertiary structural feature on the membrane-proximal intracellular face of the channel, which has been termed the 'allosteric nexus', and which is composed of a cysteine-rich linker domain and the eponymous TRP domain.[26] Breakthrough research combining cryo-electron microscopy and electrophysiology later elucidated the molecular mechanism of how the channel functions as a broad-spectrum irritant detector. With respect to electrophiles, which activate the channel by covalent modification of two cysteines in the allosteric nexus, it was shown that these reactive oxidative species act step-wise to modify two critical cysteine residues in the allosteric nexus. Upon covalent attachment, the allosteric nexus adopts a conformational change that is propagated to the channel's pore, dilating it to permit cation influx and subsequent cellular depolarization. With respect to activation by the second messenger calcium, the structure of the channel in complex with calcium localized the binding site for this ion and functional studies demonstrated that this site controls the various different effects of calcium on the channel – namely potentiation, desensitization, and receptor-operation.[27]

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.[28]

TRPA1 has also been implicated in airway irritation[29] by cigarette smoke,[30] cleaning supplies[14] and in the skin irritation experienced by some smokers trying to quit by using nicotine replacement therapies such as inhalers, sprays, or patches.[15] 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.[31]

Metabolites of paracetamol (acetaminophen) have been demonstrated to bind to the TRPA1 receptors, which may desensitize the receptors in the way capsaicin does in the spinal cord of mice, causing an antinociceptive effect. This is suggested as the antinociceptive mechanism for paracetamol.[32]

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).[33]

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.[34][35]

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.[36][37]

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.[38][39] Another example of a nonelectrophilic agent is the anesthetic propofol, which is known to cause pain on injection into a vein, a side effect attributed to TRPV1 and TRPA1 activation.[40] A dibenz[b,f][1,4]oxazepine derivative substituted by a carboxylic methyl ester at position 10 has been reported to be a potent nonelectrophilic (thiol-unreactive) TRPA1 agonist (EC50 = 0.05 nM), while dibenzoxazepine (CR 'gas', 0.3 nM) itself, as well as several other tear gases (CN (30 nM), CS (0.9 nM), CA (10 nM) 'gases') were found to be thiol-reactive TRPA1 agonists. This study found that chemical reactivity with thiols in combination with lipophilicity enabling membrane permeation result in a potent TRPA1 agonistic effect, but thiol adduct formation is neither sufficient nor necessary for TRPA1 activation.[41] 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.[16] Other TRPA1 channel activators include JT-010 and ASP-7663, while channel blockers include A-967079, HC-030031 and AM-0902.

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 the spinal cord directly activate TRPA (and also TRPV1) receptors to augment the perception of pain.[42][43][44][45] 12S-HpETE, which is the direct precursor to HxA3 and HxB3 in the ALOX12 pathway, may act only after being converted to these hepoxilins.[44] The epoxide, 5,6-epoxy-8Z,11Z,14Z-eicosatrienoic acid (5,6-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.[44]

Studies with mice, guinea pigs, and human tissues 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[46]), has been associated with ACE inhibitor-induce cough in humans.[47][48]

More recently, a peptide toxin termed the wasabi receptor toxin from the Australian black rock scorpion (Urodacus manicatus) was discovered; it was shown to bind TRPA1 non-covalently in the same region as electrophiles and act as a gating modifier toxin for the receptor, stabilizing the channel in an open conformation.[49]

TRPA1 inhibition

A number of small molecule inhibitors (antagonists) have been discovered which have been shown to block the function of TRPA1.[50] At the cellular level, assays that measure agonist-activated inhibition of TRPA1-mediated calcium fluxes and electrophysiological assays have been used to characterize the potency, species specificity and mechanism of inhibition. While the earliest inhibitors, such as HC-030031, were lower potency (micromolar inhibition) and had limited TRPA1 specificity, the more recent discovery of highly potent inhibitors with low nanomolar inhibition constants, such as A-967079 and ALGX-2542 as well as high selectivity among other members the TRP superfamily and lack of interaction with other targets have provided valuable tool compounds and candidates for future drug development.[50][51][52]

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.[53][54][55][56][57]

Ligand examples

Agonists

Gating Modifiers

Antagonists

  • HC-030031
  • GRC17536
  • A-967079
  • ALGX-2513
  • ALGX-2541
  • ALGX-2563
  • ALGX-2561
  • ALGX-2542 [50]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000104321 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032769 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Jaquemar D, Schenker T, Trueb B (March 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.
  6. ^ a b Clapham DE, Julius D, Montell C, Schultz G (December 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. S2CID 17936350.
  7. ^ a b Andersen HH, Elberling J, Arendt-Nielsen L (September 2015). "Human surrogate models of histaminergic and non-histaminergic itch". Acta Dermato-Venereologica. 95 (7): 771–7. doi:10.2340/00015555-2146. PMID 26015312.
  8. ^ a b Højland CR, Andersen HH, Poulsen JN, Arendt-Nielsen L, Gazerani P (September 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. S2CID 10418526.
  9. ^ García-Añoveros J, Nagata K (2007). "TRPA1". Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology. Vol. 179. pp. 347–62. doi:10.1007/978-3-540-34891-7_21. ISBN 978-3-540-34889-4. PMID 17217068.
  10. ^ "Entrez Gene: TRPA1 transient receptor potential cation channel, subfamily A, member 1".
  11. ^ Baraldi PG, Preti D, Materazzi S, Geppetti P (July 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.
  12. ^ Brône B, Peeters PJ, Marrannes R, Mercken M, Nuydens R, Meert T, Gijsen HJ (September 2008). "Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor". Toxicology and Applied Pharmacology. 231 (2): 150–6. Bibcode:2008ToxAP.231..150B. doi:10.1016/j.taap.2008.04.005. PMID 18501939.
  13. ^ Bessac BF, Sivula M, von Hehn CA, Caceres AI, Escalera J, Jordt SE (April 2009). "Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases". FASEB Journal. 23 (4): 1102–14. doi:10.1096/fj.08-117812. PMC 2660642. PMID 19036859.
  14. ^ a b Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE (May 2008). "TRPA1 is a major oxidant sensor in murine airway sensory neurons". The Journal of Clinical Investigation. 118 (5): 1899–910. doi:10.1172/JCI34192. PMC 2289796. PMID 18398506.
  15. ^ a b Talavera K, Gees M, Karashima Y, Meseguer VM, Vanoirbeek JA, Damann N, et al. (October 2009). "Nicotine activates the chemosensory cation channel TRPA1". Nature Neuroscience. 12 (10): 1293–9. doi:10.1038/nn.2379. hdl:10261/16906. PMID 19749751. S2CID 1670299.
  16. ^ a b Ryckmans T, Aubdool AA, Bodkin JV, Cox P, Brain SD, Dupont T, et al. (August 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.
  17. ^ Tai C, Zhu S, Zhou N (January 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. PMC 6671416. PMID 18234879.
  18. ^ Nielsen TA, Eriksen MA, Gazerani P, Andersen HH (October 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. S2CID 44150443.
  19. ^ Andersen HH, Lo Vecchio S, Gazerani P, Arendt-Nielsen L (September 2017). "Dose-response study of topical allyl isothiocyanate (mustard oil) as a human surrogate model of pain, hyperalgesia, and neurogenic inflammation" (PDF). Pain. 158 (9): 1723–1732. doi:10.1097/j.pain.0000000000000979. PMID 28614189. S2CID 23263861.
  20. ^ McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, et al. (August 2007). "TRPA1 mediates formalin-induced pain". Proceedings of the National Academy of Sciences of the United States of America. 104 (33): 13525–30. Bibcode:2007PNAS..10413525M. doi:10.1073/pnas.0705924104. PMC 1941642. PMID 17686976.
  21. ^ McMahon SB, Wood JN (March 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.
  22. ^ Sawada Y, Hosokawa H, Hori A, Matsumura K, Kobayashi S (July 2007). "Cold sensitivity of recombinant TRPA1 channels". Brain Research. 1160: 39–46. doi:10.1016/j.brainres.2007.05.047. PMID 17588549. S2CID 25946719.
  23. ^ Klionsky L, Tamir R, Gao B, Wang W, Immke DC, Nishimura N, Gavva NR (December 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.
  24. ^ Gracheva EO, Ingolia NT, Kelly YM, Cordero-Morales JF, Hollopeter G, Chesler AT, et al. (April 2010). "Molecular basis of infrared detection by snakes". Nature. 464 (7291): 1006–11. Bibcode:2010Natur.464.1006G. doi:10.1038/nature08943. PMC 2855400. PMID 20228791.
  25. ^ Geng J, Liang D, Jiang K, Zhang P (2011-12-07). "Molecular Evolution of the Infrared Sensory Gene TRPA1 in Snakes and Implications for Functional Studies". PLOS ONE. 6 (12): e28644. Bibcode:2011PLoSO...628644G. doi:10.1371/journal.pone.0028644. ISSN 1932-6203. PMC 3233596. PMID 22163322.
  26. ^ Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D (April 2015). "Structure of the TRPA1 ion channel suggests regulatory mechanisms". Nature. 520 (7548): 511–7. Bibcode:2015Natur.520..511P. doi:10.1038/nature14367. PMC 4409540. PMID 25855297.
  27. ^ Zhao J, Lin King JV, Paulsen CE, Cheng Y, Julius D (July 2020). "Irritant-evoked activation and calcium modulation of the TRPA1 receptor". Nature. 585 (7823): 141–145. Bibcode:2020Natur.585..141Z. doi:10.1038/s41586-020-2480-9. PMC 7483980. PMID 32641835. S2CID 220407248.
  28. ^ Nagatomo K, Kubo Y (November 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. Bibcode:2008PNAS..10517373N. doi:10.1073/pnas.0809769105. PMC 2582301. PMID 18988737.
  29. ^ Bessac BF, Jordt SE (December 2008). "Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control". Physiology. 23 (6): 360–70. doi:10.1152/physiol.00026.2008. PMC 2735846. PMID 19074743.
  30. ^ Andrè E, Campi B, Materazzi S, Trevisani M, Amadesi S, Massi D, et al. (July 2008). "Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents". The Journal of Clinical Investigation. 118 (7): 2574–82. doi:10.1172/JCI34886. PMC 2430498. PMID 18568077.
  31. ^ Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, Marsh S, et al. (June 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.
  32. ^ Andersson DA, Gentry C, Alenmyr L, Killander D, Lewis SE, Andersson A, et al. (November 2011). "TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ(9)-tetrahydrocannabiorcol". Nature Communications. 2 (2): 551. Bibcode:2011NatCo...2..551A. doi:10.1038/ncomms1559. PMID 22109525.
  33. ^ Miyake T, Nakamura S, Zhao M, So K, Inoue K, Numata T, et al. (September 2016). "Cold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS". Nature Communications. 7: 12840. Bibcode:2016NatCo...712840M. doi:10.1038/ncomms12840. PMC 5027619. PMID 27628562.
  34. ^ Boonen B, Startek JB, Talavera K (2016-01-01). Taste and Smell. Topics in Medicinal Chemistry. Vol. 23. Springer Berlin Heidelberg. pp. 1–41. doi:10.1007/7355_2015_98. ISBN 978-3-319-48925-4.
  35. ^ Bessac BF, Jordt SE (July 2010). "Sensory detection and responses to toxic gases: mechanisms, health effects, and countermeasures". Proceedings of the American Thoracic Society. 7 (4): 269–77. doi:10.1513/pats.201001-004SM. PMC 3136963. PMID 20601631.
  36. ^ Peyrot des Gachons C, Uchida K, Bryant B, Shima A, Sperry JB, Dankulich-Nagrudny L, et al. (January 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.
  37. ^ 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.
  38. ^ Hinman A, Chuang HH, Bautista DM, Julius D (December 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. Bibcode:2006PNAS..10319564H. doi:10.1073/pnas.0609598103. PMC 1748265. PMID 17164327.
  39. ^ a b Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG, Cravatt BF, Patapoutian A (February 2007). "Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines". Nature. 445 (7127): 541–5. Bibcode:2007Natur.445..541M. doi:10.1038/nature05544. PMID 17237762. S2CID 4344572.
  40. ^ Fischer MJ, Leffler A, Niedermirtl F, Kistner K, Eberhardt M, Reeh PW, Nau C (2010-11-05). "The general anesthetic propofol excites nociceptors by activating TRPV1 and TRPA1 rather than GABAA receptors". The Journal of Biological Chemistry. 285 (45): 34781–34792. doi:10.1074/jbc.M110.143958. ISSN 1083-351X. PMC 2966094. PMID 20826794.
  41. ^ Gijsen HJ, Berthelot D, Zaja M, Brône B, Geuens I, Mercken M (October 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.
  42. ^ Gregus AM, Doolen S, Dumlao DS, Buczynski MW, Takasusuki T, Fitzsimmons BL, et al. (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. Bibcode:2012PNAS..109.6721G. doi:10.1073/pnas.1110460109. PMC 3340022. PMID 22493235.
  43. ^ Gregus AM, Dumlao DS, Wei SC, Norris PC, Catella LC, Meyerstein FG, et al. (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.
  44. ^ a b c 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.
  45. ^ Pace-Asciak CR (April 2015). "Pathophysiology of the hepoxilins". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 383–96. doi:10.1016/j.bbalip.2014.09.007. PMID 25240838.
  46. ^ "Reference SNP (refSNP) Cluster Report: Rs11209716".
  47. ^ Maher SA, Dubuis ED, Belvisi MG (June 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.
  48. ^ Grilo A, Sáez-Rosas MP, Santos-Morano J, Sánchez E, Moreno-Rey C, Real LM, et al. (January 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. S2CID 22282464.
  49. ^ a b Lin King JV, Emrick JJ, Kelly MJ, Herzig V, King GF, Medzihradszky KF, Julius D (September 2019). "A Cell-Penetrating Scorpion Toxin Enables Mode-Specific Modulation of TRPA1 and Pain". Cell. 178 (6): 1362–1374.e16. doi:10.1016/j.cell.2019.07.014. PMC 6731142. PMID 31447178.
  50. ^ a b c Herz JM, Buated W, Thomsen W, Mori Y (2020). "Novel TRPA1 Antagonists are Multimodal Blockers of Human TRPA1 Channels: Drug Candidates for Treatment of Familial Episodic Pain Syndrome (FEPS)". The FASEB Journal. 34 (S1): 1. doi:10.1096/fasebj.2020.34.s1.02398. S2CID 218776153.
  51. ^ Herz JM, Kesicki E, Tian J, Zhu MX, Thomsen WJ (2016). A Novel Class of Potent, Allosteric TRPA1 Antagonists Reverse Hyperalgesia in Multiple Rat Models of Neuropathic Pain. Experimental Biology 2016 Meeting. Vol. 30. p. 927.3. doi:10.1096/fasebj.30.1_supplement.927.3.
  52. ^ Pryde DC, Marron B, West CG, Reister S, Amato G, Yoger K, et al. (2016-11-08). "The discovery of a potent series of carboxamide TRPA1 antagonists". MedChemComm. 7 (11): 2145–2158. doi:10.1039/C6MD00387G.
  53. ^ Qu Q, Xuan W, Fan GH (January 2015). "Roles of resolvins in the resolution of acute inflammation". Cell Biology International. 39 (1): 3–22. doi:10.1002/cbin.10345. PMID 25052386. S2CID 10160642.
  54. ^ Serhan CN, Chiang N, Dalli J, Levy BD (October 2014). "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.
  55. ^ Lim JY, Park CK, Hwang SW (2015). "Biological Roles of Resolvins and Related Substances in the Resolution of Pain". BioMed Research International. 2015: 830930. doi:10.1155/2015/830930. PMC 4538417. PMID 26339646.
  56. ^ Ji RR, Xu ZZ, Strichartz G, Serhan CN (November 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.
  57. ^ Serhan CN, Chiang N, Dalli J (May 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.
Quelle: https://en.wikipedia.org/wiki/Transient_receptor_potential_cation_channel,_member_A1