TRPA1
































































TRPA1







Available structures
PDB Ortholog search: PDBe RCSB



Identifiers
Aliases
TRPA1, ANKTM1, FEPS, transient receptor potential cation channel subfamily A member 1, FEPS1
External IDs OMIM: 604775 MGI: 3522699 HomoloGene: 7189 GeneCards: TRPA1


















Gene location (Human)
Chromosome 8 (human)
Chr. Chromosome 8 (human)[1]

Chromosome 8 (human)
Genomic location for TRPA1

Genomic location for TRPA1

Band 8q21.11 Start 72,019,917 bp[1]
End 72,075,617 bp[1]























RNA expression pattern

PBB GE TRPA1 208349 at fs.png

PBB GE TRPA1 217590 s at fs.png
More reference expression data















Orthologs
Species Human Mouse
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 Mb Chr 1: 14.87 – 14.92 Mb

PubMed search		 [3] [4]
Wikidata



View/Edit Human View/Edit Mouse

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.[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 environmental irritants giving rise to somatosensory modalities such as pain, cold and itch.[7][8]




Contents






  • 1 Function


  • 2 Clinical significance


  • 3 Ligand binding


  • 4 TRPA1 inhibition


  • 5 Ligand examples


    • 5.1 Agonists


    • 5.2 Antagonists




  • 6 References


  • 7 External links





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] 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.[10]


Recent studies indicate that TRPA1 is activated by a number of reactive [7][8][11] (allyl isothiocyanate, cinnamaldehyde, farnesyl thiosalicylic acid, formalin, hydrogen peroxide, 4-hydroxynonenal, acrolein, and tear gases[12]) and non-reactive compounds (nicotine,[13]PF-4840154[14]) and considered as a "chemosensor" in the body.[15]. TRPA1 is co-expressed with TRPV1 on nociceptive primary afferent C-fibers in humans.[16] 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.[17] 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.[18][19] 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.[20][21]


In the heat-sensitive loreal pit organs of many snakes TRPA1 is responsible for the detection of infrared radiation.[22]



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.[23]


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.[13]
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.[24]


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.[25]


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).[26]



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.[27]


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.[28][29]


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.[30][31] 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).[32] 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.[14]


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.[33][34][35][36] 12S-HpETE, which is the direct precursor to HxA3 and HxB3 in the ALOX12 pathway, may act only after being converted to these hepoxilins.[35] 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.[35]


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[37]), has been associated with ACE inhibitor-induce cough in humans.[38][39]



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.[40][41][42][43][44]



Ligand examples



Agonists



  • 4-Oxo-2-nonenal

  • Allicin

  • Allyl isothiocyanate

  • Cannabidiol

  • Gingerol

  • Icilin

  • Polygodial


  • Hepoxilins A3 and B3

  • 12S-Hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid

  • 4,5-Epoxyeicosatrienoic acid

  • CBC


  • Cinnamaldehyde[45]



Antagonists



  • HC030031

  • GRC17536

  • A-967079

  • ALGX-2513

  • ALGX-2541

  • ALGX-2563

  • ALGX-2561

  • ALGX-2542



References





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  45. ^ 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



  • TRPA1+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)









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