Transient receptor potential cation channel, member A1

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Transient receptor potential cation channel, subfamily A, member 1
Symbols TRPA1 ; ANKTM1; FEPS
External IDs OMIM604775 MGI3522699 HomoloGene7189 IUPHAR: TRPA1 ChEMBL: 6007 GeneCards: TRPA1 Gene
RNA expression pattern
PBB GE TRPA1 208349 at tn.png
PBB GE TRPA1 217590 s at tn.png
More reference expression data
Species Human Mouse
Entrez 8989 277328
Ensembl ENSG00000104321 ENSMUSG00000032769
UniProt O75762 Q8BLA8
RefSeq (mRNA) NM_007332 NM_177781
RefSeq (protein) NP_015628 NP_808449
Location (UCSC) Chr 8:
72.93 – 72.99 Mb
Chr 1:
14.87 – 14.92 Mb
PubMed search [1] [2]

Transient receptor potential cation channel, subfamily A, member 1, also known as 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, pain, cold and stretch.


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 stress sensor.[3] 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.[4]

Recent studies indicate that TRPA1 is activated by a number of reactive [5] (allyl isothiocyanate, cinnamaldehyde, farnesyl thiosalicylic acid, formalin, hydrogen peroxide, 4-hydroxynonenal, acrolein, and tear gases[6]) and non-reactive compounds (nicotine,[7] PF-4840154[8]) and considered as a 'chemosensor' in the body.[9] 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.[10][11] 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.[12][13]

In the heat-sensitive Loreal pit organs of many snakes, TRPA1 is responsible for the detection of infrared radiation.[14]

Clinical significance[edit]

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.[15]

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.[7] 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.[16]

Metabolites of paracetamol (acetaminophen) have been demonstrated to activate TRPA1 receptors in the spinal cord of mice, causing an antinociceptive effect. This is suggested as the antinociceptive mechanism for paracetamol.[17]

Ligand binding[edit]

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.[18][19]

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.[20][21] 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).[22] The pyrimidine PF-4840154 is a potent, non covalent inhibitor 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.[8]


  1. ^ Jaquemar D, Schenker T, Trueb B (March 1999). "An ankyrin-like protein with transmembrane domains is specifically lost after oncogenic transformation of human fibroblasts". J. Biol. Chem. 274 (11): 7325–33. doi:10.1074/jbc.274.11.7325. PMID 10066796. 
  3. ^ García-Añoveros J, Nagata K (2007). "TRPA1". Handb Exp Pharmacol 179 (179): 347–62. doi:10.1007/978-3-540-34891-7_21. PMID 17217068. 
  4. ^ "Entrez Gene: TRPA1 transient receptor potential cation channel, subfamily A, member 1". 
  5. ^ 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". J. Med. Chem. 53 (14): 5085–107. doi:10.1021/jm100062h. PMID 20356305. 
  6. ^ 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". Toxicol. Appl. Pharmacol. 231 (2): 150–6. doi:10.1016/j.taap.2008.04.00. PMID 18501939. 
  7. ^ a b 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 (October 2009). "Nicotine activates the chemosensory cation channel TRPA1". Nat. Neurosci. 12 (10): 1293–9. doi:10.1038/nn.2379. PMID 19749751. 
  8. ^ a b Ryckmans T, Aubdool A A, Bodkin J V, Cox P, Brain S D, Dupont T, Fairman E, Hashizume Y, Ishii N, Kato T, Kitching L, Newman J, Omoto K, Rawson D and Strover J (July 2011). "Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel". Bioorganic. Med. Chem. Lett. 21 (16): 4857–4859. doi:10.1016/j.bmcl.2011.06.035. PMID 21741838. 
  9. ^ Tai C, Zhu S, Zhou N (January 2008). "TRPA1: the central molecule for chemical sensing in pain pathway?". J. Neurosci. 28 (5): 1019–21. doi:10.1523/JNEUROSCI.5237-07.2008. PMID 18234879. 
  10. ^ McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM, Fanger CM (August 2007). "TRPA1 mediates formalin-induced pain". Proc. Natl. Acad. Sci. U.S.A. 104 (33): 13525–30. doi:10.1073/pnas.0705924104. PMC 1941642. PMID 17686976. 
  11. ^ 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. 
  12. ^ Sawada Y, Hosokawa H, Hori A, Matsumura K, Kobayashi S (July 2007). "Cold sensitivity of recombinant TRPA1 channels". Brain Res. 1160: 39–46. doi:10.1016/j.brainres.2007.05.047. PMID 17588549. 
  13. ^ 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". Mol Pain 3: 39. doi:10.1186/1744-8069-3-39. PMC 2222611. PMID 18086308. 
  14. ^ Gracheva EO, Ingolia NT, Kelly YM, Cordero-Morales JF, Hollopeter G, Chesler AT, Sánchez EE, Perez JC, Weissman JS, Julius D (April 2010). "Molecular basis of infrared detection by snakes". Nature 464 (7291): 1006–11. doi:10.1038/nature08943. PMC 2855400. PMID 20228791. 
  15. ^ Nagatomo K, Kubo Y (November 2008). "Caffeine activates mouse TRPA1 channels but suppresses human TRPA1 channels". Proc. Natl. Acad. Sci. U.S.A. 105 (45): 17373–8. doi:10.1073/pnas.0809769105. PMC 2582301. PMID 18988737. 
  16. ^ Kremeyer B et al. (June 2010). "A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome". Neuron 66 (5): 671–680. doi:10.1016/j.neuron.2010.04.030. PMID 20547126. 
  17. ^ Andersson, David (2011-11-22). "TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol". Nature Communications 2 (2): 551. doi:10.1038/ncomms1559. PMID 22109525. 
  18. ^ Peyrot des Gachons C, Uchida K, Bryant B, Shima A, Sperry JB, Dankulich-Nagrudny L, Tominaga M, Smith AB, Beauchamp GK, Breslin PA (January 2011). "Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal". J. Neurosci. 31 (3): 999–1009. doi:10.1523/JNEUROSCI.1374-10.2011. PMC 3073417. PMID 21248124. 
  19. ^ 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". Chem. Senses 34 (4): 333–9. doi:10.1093/chemse/bjp006. PMID 19273462. 
  20. ^ Hinman A, Chuang HH, Bautista DM, Julius D (December 2006). "TRP channel activation by reversible covalent modification". Proc. Natl. Acad. Sci. U.S.A. 103 (51): 19564–8. doi:10.1073/pnas.0609598103. PMC 1748265. PMID 17164327. 
  21. ^ 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. doi:10.1038/nature05544. PMID 17237762. 
  22. ^ 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". J Med Chem 53 (19): 7011–7020. doi:10.1021/jm100477n. PMID 20806939. 

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External links[edit]