Target Information

Target General Infomation
Target ID
T84040
Former ID
TTDS00465
Target Name
Transient receptor potential cation channel subfamily A member 1
Gene Name
TRPA1
Synonyms
ANKTM1; Ankyrin-like with transmembrane domains protein 1; Transformation-sensitive protein p120; TRPA1
Target Type
Successful
Disease Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Throat irritation [ICD9: 478.29; ICD10: J39.2]
Function
Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function. Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes. Acts also as a ionotropic cannabinoid receptor by being activated by delta(9)- tetrahydrocannabinol (THC), the psychoactive component of marijuana. Not involved in menthol sensation. May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).
BioChemical Class
Transient receptor potential catioin channel
Target Validation
T84040
UniProt ID
O75762
Sequence
MKRSLRKMWRPGEKKEPQGVVYEDVPDDTEDFKESLKVVFEGSAYGLQNFNKQKKLKRCD
DMDTFFLHYAAAEGQIELMEKITRDSSLEVLHEMDDYGNTPLHCAVEKNQIESVKFLLSR
GANPNLRNFNMMAPLHIAVQGMNNEVMKVLLEHRTIDVNLEGENGNTAVIIACTTNNSEA
LQILLKKGAKPCKSNKWGCFPIHQAAFSGSKECMEIILRFGEEHGYSRQLHINFMNNGKA
TPLHLAVQNGDLEMIKMCLDNGAQIDPVEKGRCTAIHFAATQGATEIVKLMISSYSGSVD
IVNTTDGCHETMLHRASLFDHHELADYLISVGADINKIDSEGRSPLILATASASWNIVNL
LLSKGAQVDIKDNFGRNFLHLTVQQPYGLKNLRPEFMQMQQIKELVMDEDNDGCTPLHYA
CRQGGPGSVNNLLGFNVSIHSKSKDKKSPLHFAASYGRINTCQRLLQDISDTRLLNEGDL
HGMTPLHLAAKNGHDKVVQLLLKKGALFLSDHNGWTALHHASMGGYTQTMKVILDTNLKC
TDRLDEDGNTALHFAAREGHAKAVALLLSHNADIVLNKQQASFLHLALHNKRKEVVLTII
RSKRWDECLKIFSHNSPGNKCPITEMIEYLPECMKVLLDFCMLHSTEDKSCRDYYIEYNF
KYLQCPLEFTKKTPTQDVIYEPLTALNAMVQNNRIELLNHPVCKEYLLMKWLAYGFRAHM
MNLGSYCLGLIPMTILVVNIKPGMAFNSTGIINETSDHSEILDTTNSYLIKTCMILVFLS
SIFGYCKEAGQIFQQKRNYFMDISNVLEWIIYTTGIIFVLPLFVEIPAHLQWQCGAIAVY
FYWMNFLLYLQRFENCGIFIVMLEVILKTLLRSTVVFIFLLLAFGLSFYILLNLQDPFSS
PLLSIIQTFSMMLGDINYRESFLEPYLRNELAHPVLSFAQLVSFTIFVPIVLMNLLIGLA
VGDIAEVQKHASLKRIAMQVELHTSLEKKLPLWFLRKVDQKSTIVYPNKPRSGGMLFHIF
CFLFCTGEIRQEIPNADKSLEMEILKQKYRLKDLTFLLEKQHELIKLIIQKMEIISETED
DDSHCSFQDRFKKEQMEQRNSRWNTVLRAVKAKTHHLEP
Structure
1UOH
Drugs and Mode of Action
Drug(s) Menthol Drug Info Approved Throat irritation [1], [2]
Activator 1'-acetoxychavicol acetate Drug Info [3]
1,6-hexamethylene diisocyanate Drug Info [4]
2-pentenal Drug Info [5]
4-oxo-nonenal Drug Info [6]
acetaldehyde Drug Info [7]
acrolein Drug Info [8]
artepillin C Drug Info [9]
benzyl bromide Drug Info [4]
bromoacetone Drug Info [4]
chlorobenzylidene malononitrile Drug Info [10]
chloropicrin Drug Info [4]
cinnamaldehyde Drug Info [11]
crotylaldehyde Drug Info [12]
dibenzoxazepine Drug Info [10]
dibutyl phthalate Drug Info [13]
formalin Drug Info [14]
gingerol Drug Info [11]
icilin Drug Info [15]
isovelleral Drug Info [16]
Menthol Drug Info [17]
methyl isocyanate Drug Info [4]
methyl p-hydroxybenzoate Drug Info [18]
methyl salicylate Drug Info [11]
methylglyoxal Drug Info [19]
morphanthridine Drug Info [10]
MTSEA Drug Info [20]
nitrooleic acid Drug Info [21]
NPPB Drug Info [22]
oleocanthal Drug Info [23]
omega-chloroacetophenone Drug Info [10]
PF-4840154 Drug Info [24]
prostaglandin A2 Drug Info [25]
super cinnamaldehyde Drug Info [20]
Inhibitor 2-methyl-1-(pyridin-3-yl)pent-1-en-3-one oxime Drug Info [26]
2-methyl-1-(pyridin-4-yl)pent-1-en-3-one oxime Drug Info [26]
2-methyl-1-(thiophen-2-yl)pent-1-en-3-one oxime Drug Info [26]
2-methyl-1-(thiophen-3-yl)pent-1-en-3-one oxime Drug Info [26]
3-Methyl-4-phenylbut-3-en-2-one oxime Drug Info [27]
AMG-2504 Drug Info [26]
AMG-5445 Drug Info [26]
AMG-7160 Drug Info [26]
AMG-9090 Drug Info [26]
AP18 5 Drug Info [26]
Antagonist A-967079 Drug Info [28]
TRPA1 antagonists Drug Info [28]
Blocker (channel blocker) AP18 Drug Info [29]
Inhibitor (gating inhibitor) resolvin D1 Drug Info [30]
resolvin D2 Drug Info [31]
TCS 5861528 Drug Info [32]
Pathways
KEGG Pathway Inflammatory mediator regulation of TRP channels
Reactome TRP channels
References
REF 1FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 022029.
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2471).
REF 3Galangal pungent component, 1'-acetoxychavicol acetate, activates TRPA1. Biosci Biotechnol Biochem. 2010;74(8):1694-6. Epub 2010 Aug 7.
REF 4Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases. FASEB J. 2009 Apr;23(4):1102-14.
REF 5Transient receptor potential ankyrin 1 (TRPA1) channel as emerging target for novel analgesics and anti-inflammatory agents. J Med Chem. 2010 Jul 22;53(14):5085-107.
REF 6Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci. 2008 Mar 5;28(10):2485-94.
REF 7Transient receptor potential A1 mediates acetaldehyde-evoked pain sensation. Eur J Neurosci. 2007 Nov;26(9):2516-23. Epub 2007 Oct 23.
REF 8TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006 Mar 24;124(6):1269-82.
REF 9Artepillin C, a major ingredient of Brazilian propolis, induces a pungent taste by activating TRPA1 channels. PLoS One. 2012;7(11):e48072.
REF 10Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor. Toxicol Appl Pharmacol. 2008 Sep 1;231(2):150-6.
REF 11Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron. 2004 Mar 25;41(6):849-57.
REF 12Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J Clin Invest. 2008 Jul;118(7):2574-82.
REF 13TRPA1 and TRPV1 activation is a novel adjuvant effect mechanism in contact hypersensitivity. J Neuroimmunol. 2009 Feb 15;207(1-2):66-74.
REF 14An ion channel essential for sensing chemical damage. J Neurosci. 2007 Oct 17;27(42):11412-5.
REF 15ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003 Mar 21;112(6):819-29.
REF 16TRPA1 mediates the noxious effects of natural sesquiterpene deterrents. J Biol Chem. 2008 Aug 29;283(35):24136-44.
REF 17TRPV1-mediated itch in seasonal allergic rhinitis. Allergy. 2009 May;64(5):807-10. Epub 2009 Feb 13.
REF 18Methyl p-hydroxybenzoate causes pain sensation through activation of TRPA1 channels. Br J Pharmacol. 2007 May;151(1):153-60. Epub 2007 Mar 12.
REF 19Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy. Pharmacol Res. 2012 Jan;65(1):149-58.
REF 20Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature. 2007 Feb 1;445(7127):541-5. Epub 2007 Jan 21.
REF 21Nitrooleic acid, an endogenous product of nitrative stress, activates nociceptive sensory nerves via the direct activation of TRPA1. Mol Pharmacol. 2009 Apr;75(4):820-9.
REF 22NPPB structure-specifically activates TRPA1 channels. Biochem Pharmacol. 2010 Jul 1;80(1):113-21.
REF 23Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal. J Neurosci. 2011 Jan 19;31(3):999-1009.
REF 24Design and pharmacological evaluation of PF-4840154, a non-electrophilic reference agonist of the TrpA1 channel. Bioorg Med Chem Lett. 2011 Aug 15;21(16):4857-9.
REF 25Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):12045-50.
REF 26Transient receptor potential ankyrin 1 (TRPA1) channel as emerging target for novel analgesics and anti-inflammatory agents. J Med Chem. 2010 Jul 22;53(14):5085-107. doi: 10.1021/jm100062h.
REF 27Bioorg Med Chem Lett. 2010 Jan 1;20(1):276-9. Epub 2009 Oct 30.Oxime derivatives related to AP18: Agonists and antagonists of the TRPA1 receptor.
REF 28(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 485).
REF 29A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol Pain. 2007 Dec 17;3:40.
REF 30Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception. Br J Pharmacol. 2010 Oct;161(3):707-20.
REF 31Resolvin D2 is a potent endogenous inhibitor for transient receptor potential subtype V1/A1, inflammatory pain, and spinal cord synaptic plasticity in mice: distinct roles of resolvin D1, D2, and E1.J Neurosci. 2011 Dec 14;31(50):18433-8.
REF 32Attenuation of mechanical hypersensitivity by an antagonist of the TRPA1 ion channel in diabetic animals. Anesthesiology. 2009 Jul;111(1):147-54.

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