ID TRPA1_HUMAN Reviewed; 1119 AA. AC O75762; A6NIN6; DT 21-DEC-2004, integrated into UniProtKB/Swiss-Prot. DT 30-NOV-2010, sequence version 3. DT 27-MAR-2024, entry version 181. DE RecName: Full=Transient receptor potential cation channel subfamily A member 1 {ECO:0000312|HGNC:HGNC:497}; DE AltName: Full=Ankyrin-like with transmembrane domains protein 1 {ECO:0000312|HGNC:HGNC:497}; DE AltName: Full=Transformation-sensitive protein p120 {ECO:0000303|PubMed:10066796}; DE Short=p120 {ECO:0000303|PubMed:10066796}; DE AltName: Full=Wasabi receptor {ECO:0000303|PubMed:25855297, ECO:0000303|PubMed:31447178}; GN Name=TRPA1 {ECO:0000312|HGNC:HGNC:497}; GN Synonyms=ANKTM1 {ECO:0000312|HGNC:HGNC:497}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND RP VARIANTS CYS-3; THR-58 AND ASN-186. RC TISSUE=Lung; RX PubMed=10066796; DOI=10.1074/jbc.274.11.7325; RA Jaquemar D., Schenker T., Trueb B.; RT "An ankyrin-like protein with transmembrane domains is specifically lost RT after oncogenic transformation of human fibroblasts."; RL J. Biol. Chem. 274:7325-7333(1999). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., RA Platzer M., Shimizu N., Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [3] RP ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-621; CYS-641; CYS-665 AND RP LYS-710. RX PubMed=17164327; DOI=10.1073/pnas.0609598103; RA Hinman A., Chuang H.H., Bautista D.M., Julius D.; RT "TRP channel activation by reversible covalent modification."; RL Proc. Natl. Acad. Sci. U.S.A. 103:19564-19568(2006). RN [4] RP ACTIVITY REGULATION. RX PubMed=17567811; DOI=10.1523/jneurosci.0623-07.2007; RA Kim D., Cavanaugh E.J.; RT "Requirement of a soluble intracellular factor for activation of transient RT receptor potential A1 by pungent chemicals: role of inorganic RT polyphosphates."; RL J. Neurosci. 27:6500-6509(2007). RN [5] RP FUNCTION, ACTIVITY REGULATION, HYDROXYLATION AT PRO-394, OXIDATION AT RP CYS-633 AND CYS-856, MUTAGENESIS OF CYS-173; CYS-192; PRO-394; CYS-621; RP CYS-633; CYS-641; CYS-665 AND CYS-856, AND SUBCELLULAR LOCATION. RX PubMed=21873995; DOI=10.1038/nchembio.640; RA Takahashi N., Kuwaki T., Kiyonaka S., Numata T., Kozai D., Mizuno Y., RA Yamamoto S., Naito S., Knevels E., Carmeliet P., Oga T., Kaneko S., RA Suga S., Nokami T., Yoshida J., Mori Y.; RT "TRPA1 underlies a sensing mechanism for O2."; RL Nat. Chem. Biol. 7:701-711(2011). RN [6] RP ACTIVITY REGULATION. RX PubMed=21402443; DOI=10.1016/j.pain.2011.01.049; RA Chen J., Joshi S.K., DiDomenico S., Perner R.J., Mikusa J.P., Gauvin D.M., RA Segreti J.A., Han P., Zhang X.F., Niforatos W., Bianchi B.R., Baker S.J., RA Zhong C., Simler G.H., McDonald H.A., Schmidt R.G., McGaraughty S.P., RA Chu K.L., Faltynek C.R., Kort M.E., Reilly R.M., Kym P.R.; RT "Selective blockade of TRPA1 channel attenuates pathological pain without RT altering noxious cold sensation or body temperature regulation."; RL Pain 152:1165-1172(2011). RN [7] RP FUNCTION. RX PubMed=23199233; DOI=10.1186/1745-9974-8-11; RA Buday T., Brozmanova M., Biringerova Z., Gavliakova S., Poliacek I., RA Calkovsky V., Shetthalli M.V., Plevkova J.; RT "Modulation of cough response by sensory inputs from the nose - role of RT trigeminal TRPA1 versus TRPM8 channels."; RL Cough 8:11-11(2012). RN [8] RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND ACTIVATION BY ELECTROPHILES. RX PubMed=25389312; DOI=10.1073/pnas.1412689111; RA Moparthi L., Survery S., Kreir M., Simonsen C., Kjellbom P., RA Hoegestaett E.D., Johanson U., Zygmunt P.M.; RT "Human TRPA1 is intrinsically cold- and chemosensitive with and without its RT N-terminal ankyrin repeat domain."; RL Proc. Natl. Acad. Sci. U.S.A. 111:16901-16906(2014). RN [9] RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF LYS-620; CYS-621 AND RP CYS-665. RX PubMed=27241698; DOI=10.1085/jgp.201611581; RA Bahia P.K., Parks T.A., Stanford K.R., Mitchell D.A., Varma S., RA Stevens S.M. Jr., Taylor-Clark T.E.; RT "The exceptionally high reactivity of Cys 621 is critical for electrophilic RT activation of the sensory nerve ion channel TRPA1."; RL J. Gen. Physiol. 147:451-465(2016). RN [10] RP MUTAGENESIS OF PRO-622; MET-634 AND THR-646, AND SUBUNIT. RX PubMed=31447178; DOI=10.1016/j.cell.2019.07.014; RA Lin King J.V., Emrick J.J., Kelly M.J.S., Herzig V., King G.F., RA Medzihradszky K.F., Julius D.; RT "A cell-penetrating scorpion toxin enables mode-specific modulation of RT TRPA1 and pain."; RL Cell 178:1362-1374(2019). RN [11] RP MUTAGENESIS OF CYS-621; PHE-909 AND PHE-944, AND ACTIVITY REGULATION. RX PubMed=30878828; DOI=10.1016/j.ejmech.2019.02.074; RA Chandrabalan A., McPhillie M.J., Morice A.H., Boa A.N., Sadofsky L.R.; RT "N-Cinnamoylanthranilates as human TRPA1 modulators: structure-activity RT relationships and channel binding sites."; RL Eur. J. Med. Chem. 170:141-156(2019). RN [12] RP STRUCTURE BY ELECTRON MICROSCOPY (4.24 ANGSTROMS) IN COMPLEXES WITH RP SYNTHETIC AGONISTS, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, DOMAIN, AND RP MUTAGENESIS OF PHE-909. RX PubMed=25855297; DOI=10.1038/nature14367; RA Paulsen C.E., Armache J.P., Gao Y., Cheng Y., Julius D.; RT "Structure of the TRPA1 ion channel suggests regulatory mechanisms."; RL Nature 520:511-517(2015). RN [13] RP ERRATUM OF PUBMED:25855297. RX PubMed=26200340; DOI=10.1038/nature14871; RA Paulsen C.E., Armache J.P., Gao Y., Cheng Y., Julius D.; RL Nature 525:552-552(2015). RN [14] RP VARIANT FEPS1 SER-855, CHARACTERIZATION OF VARIANT FEPS1 SER-855, FUNCTION, RP SUBCELLULAR LOCATION, AND ACTIVITY REGULATION. RX PubMed=20547126; DOI=10.1016/j.neuron.2010.04.030; RA Kremeyer B., Lopera F., Cox J.J., Momin A., Rugiero F., Marsh S., RA Woods C.G., Jones N.G., Paterson K.J., Fricker F.R., Villegas A., RA Acosta N., Pineda-Trujillo N.G., Ramirez J.D., Zea J., Burley M.W., RA Bedoya G., Bennett D.L., Wood J.N., Ruiz-Linares A.; RT "A gain-of-function mutation in TRPA1 causes familial episodic pain RT syndrome."; RL Neuron 66:671-680(2010). CC -!- FUNCTION: Receptor-activated non-selective cation channel involved in CC pain detection and possibly also in cold perception, oxygen CC concentration perception, cough, itch, and inner ear function CC (PubMed:21873995, PubMed:23199233, PubMed:25389312, PubMed:25855297). CC Shows 8-fold preference for divalent over monovalent cations CC (PubMed:31447178). Has a central role in the pain response to CC endogenous inflammatory mediators and to a diverse array of irritants, CC such as allylthiocyanate (AITC) from mustard oil or wasabi, CC cinnamaldehyde, diallyl disulfide (DADS) from garlic, and acrolein, an CC irritant from tears gas and vehicle exhaust fumes (PubMed:25389312, CC PubMed:27241698, PubMed:30878828, PubMed:20547126). Acts also as an CC ionotropic cannabinoid receptor by being activated by delta(9)- CC tetrahydrocannabinol (THC), the psychoactive component of marijuana CC (PubMed:25389312). Is activated by a large variety of structurally CC unrelated electrophilic and non-electrophilic chemical compounds. CC Electrophilic ligands activate TRPA1 by interacting with critical N- CC terminal Cys residues in a covalent manner, whereas mechanisms of non- CC electrophilic ligands are not well determined. May be a component for CC the mechanosensitive transduction channel of hair cells in inner ear, CC thereby participating in the perception of sounds. Probably operated by CC a phosphatidylinositol second messenger system (By similarity). CC {ECO:0000250|UniProtKB:Q8BLA8, ECO:0000269|PubMed:20547126, CC ECO:0000269|PubMed:21873995, ECO:0000269|PubMed:25389312, CC ECO:0000269|PubMed:25855297, ECO:0000269|PubMed:27241698, CC ECO:0000269|PubMed:30878828, ECO:0000269|PubMed:31447178, CC ECO:0000305|PubMed:23199233}. CC -!- ACTIVITY REGULATION: A cytosolic factor (probably pyrophosphate, CC polytriphosphate, polyP4, polyP25, polyP45, and/or polyP65) is CC necessary for TRPA1 activation by irritants (PubMed:17567811). Such CC factor acts by keeping TRPA1 in a agonist-sensitive state CC (PubMed:17567811). Inhibited by the potent blocker of TRPV channels CC ruthenium red, A-967079, AP-18, HC-030031, and aryl sulfonamide CC derivative (S)-N-(4-chlorobenzyl)-1-((4- CC fluorophenyl)sulfonyl)pyrrolidine-2-carboxamide (ASD) (PubMed:17567811, CC PubMed:21873995, PubMed:21402443, PubMed:30878828, PubMed:20547126). CC Non-covalently activated by the scorpion wasabi receptor toxin CC (PubMed:31447178). Activated by benzyl isothiocyanate (BITC), CC iodoacetamide, sulfhydryl reactive agent MTSEA, N-methyl maleimide CC (NMM), N-ethylmaleimide (NEM), and 2-aminoethyldiphenylborinate (2-APB) CC (PubMed:17164327, PubMed:17567811, PubMed:21873995, PubMed:27241698). CC Also activated by hyperoxia (PubMed:21873995). CC {ECO:0000269|PubMed:17164327, ECO:0000269|PubMed:17567811, CC ECO:0000269|PubMed:20547126, ECO:0000269|PubMed:21402443, CC ECO:0000269|PubMed:21873995, ECO:0000269|PubMed:27241698, CC ECO:0000269|PubMed:30878828, ECO:0000269|PubMed:31447178}. CC -!- SUBUNIT: Homotetramer (PubMed:25389312, PubMed:25855297). Interacts CC with TMEM100 (By similarity). Interacts with EGLN1 (By similarity). CC Interacts with the scorpion wasabi receptor toxin at the same site that CC electrophiles but in a non-covalent manner (PubMed:31447178). CC {ECO:0000250|UniProtKB:Q8BLA8, ECO:0000269|PubMed:25389312, CC ECO:0000269|PubMed:25855297, ECO:0000269|PubMed:31447178}. CC -!- INTERACTION: CC O75762; O75762: TRPA1; NbExp=2; IntAct=EBI-11722999, EBI-11722999; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20547126, CC ECO:0000269|PubMed:21873995, ECO:0000269|PubMed:25389312, CC ECO:0000269|PubMed:25855297}; Multi-pass membrane protein CC {ECO:0000305}. CC -!- TISSUE SPECIFICITY: Expressed at very low levels in fibroblasts. CC {ECO:0000269|PubMed:10066796}. CC -!- DEVELOPMENTAL STAGE: Expressed in embryos at 12 weeks of age. CC {ECO:0000269|PubMed:10066796}. CC -!- DOMAIN: C-terminal helices from the four subunits associate to form CC atypical coiled coil structure; this region is probably involved in CC binding the inositol polyphosphates that are required for optimal CC channel activity (in vitro). {ECO:0000305|PubMed:25855297}. CC -!- DOMAIN: The ANK repeat domain consists of a convex stem structure CC formed by five ANK repeats and 11 additional ANK repeats that form a CC crescent-shaped structure that surrounds the protein core. CC {ECO:0000269|PubMed:25855297}. CC -!- PTM: TRPA1 activation by electrophiles occurs though covalent CC modification of specific cysteine residues in the N-terminal CC cytoplasmic domain (PubMed:25389312). {ECO:0000305|PubMed:25389312}. CC -!- PTM: Hydroxylation is required for TRPA1 activity inhibition in CC normoxia. In hypoxia, the decrease in oxygen concentration diminishes CC the activity of the hydroxylase EGLN1, thus relieving TRPA1 from CC inhibition and ultimately leading to channel activation. CC {ECO:0000269|PubMed:21873995}. CC -!- PTM: Oxidation of Cys-633 and Cys-856 in hyperoxia may override the CC hydroxylase EGLN1-mediated inhibition, causing TRPA1 activation. CC {ECO:0000269|PubMed:21873995}. CC -!- DISEASE: Episodic pain syndrome, familial, 1 (FEPS1) [MIM:615040]: An CC autosomal dominant neurologic disorder characterized by onset in CC infancy of episodic debilitating upper body pain triggered by fasting, CC cold, and physical stress. The period of intense pain is accompanied by CC breathing difficulties, tachycardia, sweating, generalized pallor, CC peribuccal cyanosis, and stiffness of the abdominal wall. Affected CC individuals do not manifest altered pain sensitivity outside the CC episodes. {ECO:0000269|PubMed:20547126}. Note=The disease is caused by CC variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the transient receptor (TC 1.A.4) family. CC {ECO:0000305}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The power behind pain CC - Issue 82 of May 2007; CC URL="https://web.expasy.org/spotlight/back_issues/082"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Y10601; CAA71610.1; -; mRNA. DR EMBL; AC022867; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS34908.1; -. DR RefSeq; NP_015628.2; NM_007332.2. DR RefSeq; XP_011515927.1; XM_011517625.2. DR RefSeq; XP_016869435.1; XM_017013946.1. DR PDB; 3J9P; EM; 4.24 A; A/B/C/D=2-1119. DR PDB; 6HC8; X-ray; 1.90 A; E=313-339. DR PDB; 6PQO; EM; 2.88 A; A/B/C/D=2-1119. DR PDB; 6PQP; EM; 3.06 A; A/B/C/D=2-1119. DR PDB; 6PQQ; EM; 2.81 A; A/B/C/D=2-1119. DR PDB; 6V9V; EM; 2.60 A; A/B/C/D=1-1119. DR PDB; 6V9W; EM; 3.10 A; A/B/C/D=1-1119. DR PDB; 6V9X; EM; 3.30 A; A/B/C/D=1-1119. DR PDB; 6V9Y; EM; 3.60 A; A/B/C/D=1-1119. DR PDB; 6WJ5; EM; 3.60 A; A/B/C/D=448-1078. DR PDB; 6X2J; EM; 3.00 A; A/B/C/D=448-1078. DR PDB; 7JUP; EM; 3.05 A; A/B/C/D=448-1078. DR PDB; 7OR0; EM; 2.64 A; A/B/C/D=1-1119. DR PDB; 7OR1; EM; 2.64 A; A/B/C/D=1-1119. DR PDBsum; 3J9P; -. DR PDBsum; 6HC8; -. DR PDBsum; 6PQO; -. DR PDBsum; 6PQP; -. DR PDBsum; 6PQQ; -. DR PDBsum; 6V9V; -. DR PDBsum; 6V9W; -. DR PDBsum; 6V9X; -. DR PDBsum; 6V9Y; -. DR PDBsum; 6WJ5; -. DR PDBsum; 6X2J; -. DR PDBsum; 7JUP; -. DR PDBsum; 7OR0; -. DR PDBsum; 7OR1; -. DR AlphaFoldDB; O75762; -. DR EMDB; EMD-13036; -. DR EMDB; EMD-13037; -. DR EMDB; EMD-20449; -. DR EMDB; EMD-20450; -. DR EMDB; EMD-20451; -. DR EMDB; EMD-21127; -. DR EMDB; EMD-21128; -. DR EMDB; EMD-21129; -. DR EMDB; EMD-21130; -. DR EMDB; EMD-21131; -. DR EMDB; EMD-21688; -. DR EMDB; EMD-22009; -. DR EMDB; EMD-22490; -. DR EMDB; EMD-6267; -. DR EMDB; EMD-6268; -. DR EMDB; EMD-6269; -. DR SMR; O75762; -. DR BioGRID; 114471; 6. DR DIP; DIP-61520N; -. DR IntAct; O75762; 3. DR MINT; O75762; -. DR STRING; 9606.ENSP00000262209; -. DR BindingDB; O75762; -. DR ChEMBL; CHEMBL6007; -. DR DrugBank; DB11345; (S)-camphor. DR DrugBank; DB11148; Butamben. DR DrugBank; DB01744; Camphor. DR DrugBank; DB09061; Cannabidiol. DR DrugBank; DB14050; Cannabidivarin. DR DrugBank; DB00825; Levomenthol. DR DrugBank; DB14009; Medical Cannabis. DR DrugBank; DB14011; Nabiximols. DR DrugBank; DB11755; Tetrahydrocannabivarin. DR DrugCentral; O75762; -. DR GuidetoPHARMACOLOGY; 485; -. DR TCDB; 1.A.4.6.3; the transient receptor potential ca2+/cation channel (trp-cc) family. DR GlyCosmos; O75762; 2 sites, No reported glycans. DR GlyGen; O75762; 2 sites. DR iPTMnet; O75762; -. DR PhosphoSitePlus; O75762; -. DR BioMuta; TRPA1; -. DR jPOST; O75762; -. DR MassIVE; O75762; -. DR PaxDb; 9606-ENSP00000262209; -. DR PeptideAtlas; O75762; -. DR ProteomicsDB; 50181; -. DR Antibodypedia; 12262; 328 antibodies from 33 providers. DR DNASU; 8989; -. DR Ensembl; ENST00000262209.5; ENSP00000262209.4; ENSG00000104321.11. DR GeneID; 8989; -. DR KEGG; hsa:8989; -. DR MANE-Select; ENST00000262209.5; ENSP00000262209.4; NM_007332.3; NP_015628.2. DR UCSC; uc003xza.4; human. DR AGR; HGNC:497; -. DR CTD; 8989; -. DR DisGeNET; 8989; -. DR GeneCards; TRPA1; -. DR HGNC; HGNC:497; TRPA1. DR HPA; ENSG00000104321; Tissue enhanced (intestine, stomach, urinary bladder). DR MalaCards; TRPA1; -. DR MIM; 604775; gene. DR MIM; 615040; phenotype. DR neXtProt; NX_O75762; -. DR OpenTargets; ENSG00000104321; -. DR Orphanet; 581271; Cramp-fasciculation syndrome. DR Orphanet; 391389; Familial episodic pain syndrome with predominantly upper body involvement. DR VEuPathDB; HostDB:ENSG00000104321; -. DR eggNOG; KOG0510; Eukaryota. DR GeneTree; ENSGT00940000156118; -. DR InParanoid; O75762; -. DR OMA; HWATEKN; -. DR OrthoDB; 2910129at2759; -. DR PhylomeDB; O75762; -. DR TreeFam; TF317264; -. DR PathwayCommons; O75762; -. DR Reactome; R-HSA-3295583; TRP channels. DR SignaLink; O75762; -. DR BioGRID-ORCS; 8989; 6 hits in 1151 CRISPR screens. DR GenomeRNAi; 8989; -. DR Pharos; O75762; Tclin. DR PRO; PR:O75762; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; O75762; Protein. DR Bgee; ENSG00000104321; Expressed in oocyte and 110 other cell types or tissues. DR ExpressionAtlas; O75762; baseline and differential. DR GO; GO:0005886; C:plasma membrane; IMP:UniProtKB. DR GO; GO:0032421; C:stereocilium bundle; IEA:Ensembl. DR GO; GO:0005262; F:calcium channel activity; TAS:Reactome. DR GO; GO:0015278; F:calcium-release channel activity; IDA:UniProtKB. DR GO; GO:0015267; F:channel activity; TAS:ProtInc. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0097604; F:temperature-gated cation channel activity; IDA:UniProtKB. DR GO; GO:0070588; P:calcium ion transmembrane transport; IMP:UniProtKB. DR GO; GO:0007166; P:cell surface receptor signaling pathway; IEA:Ensembl. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IDA:MGI. DR GO; GO:0071310; P:cellular response to organic substance; IEA:Ensembl. DR GO; GO:0050968; P:detection of chemical stimulus involved in sensory perception of pain; IEA:Ensembl. DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; IEA:Ensembl. DR GO; GO:0006874; P:intracellular calcium ion homeostasis; IDA:MGI. DR GO; GO:0006811; P:monoatomic ion transport; TAS:ProtInc. DR GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB. DR GO; GO:0009409; P:response to cold; IEA:Ensembl. DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl. DR GO; GO:0010033; P:response to organic substance; IMP:UniProtKB. DR GO; GO:0048265; P:response to pain; IEA:Ensembl. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0019233; P:sensory perception of pain; IMP:UniProtKB. DR GO; GO:0050955; P:thermoception; IEA:Ensembl. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 5. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR005821; Ion_trans_dom. DR PANTHER; PTHR47143; TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL PROTEIN PAINLESS; 1. DR PANTHER; PTHR47143:SF3; TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL PROTEIN PAINLESS; 1. DR Pfam; PF00023; Ank; 2. DR Pfam; PF12796; Ank_2; 5. DR Pfam; PF00520; Ion_trans; 1. DR PRINTS; PR01415; ANKYRIN. DR SMART; SM00248; ANK; 14. DR SUPFAM; SSF48403; Ankyrin repeat; 2. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 9. DR Genevisible; O75762; HS. PE 1: Evidence at protein level; KW 3D-structure; ANK repeat; Cell membrane; Coiled coil; Disease variant; KW Disulfide bond; Glycoprotein; Hydroxylation; Ion channel; Ion transport; KW Membrane; Oxidation; Reference proteome; Repeat; Sensory transduction; KW Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..1119 FT /note="Transient receptor potential cation channel FT subfamily A member 1" FT /id="PRO_0000215369" FT TOPO_DOM 1..719 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:25855297" FT TRANSMEM 720..740 FT /note="Helical; Name=1" FT /evidence="ECO:0000305|PubMed:25855297" FT TOPO_DOM 741..764 FT /note="Extracellular" FT /evidence="ECO:0000305|PubMed:25855297" FT TRANSMEM 765..785 FT /note="Helical; Name=2" FT /evidence="ECO:0000305|PubMed:25855297" FT TOPO_DOM 786..803 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:25855297" FT TRANSMEM 804..824 FT /note="Helical; Name=3" FT /evidence="ECO:0000305|PubMed:25855297" FT TOPO_DOM 825..829 FT /note="Extracellular" FT /evidence="ECO:0000305|PubMed:25855297" FT TRANSMEM 830..850 FT /note="Helical; Name=4" FT /evidence="ECO:0000305|PubMed:25855297" FT TOPO_DOM 851..873 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:25855297" FT TRANSMEM 874..894 FT /note="Helical; Name=5" FT /evidence="ECO:0000305|PubMed:25855297" FT TOPO_DOM 895..901 FT /note="Extracellular" FT /evidence="ECO:0000305|PubMed:25855297" FT INTRAMEM 902..922 FT /note="Pore-forming" FT /evidence="ECO:0000305|PubMed:25855297" FT TOPO_DOM 923..934 FT /note="Extracellular" FT /evidence="ECO:0000305|PubMed:25855297" FT TRANSMEM 935..956 FT /note="Helical; Name=6" FT /evidence="ECO:0000305|PubMed:25855297" FT TOPO_DOM 957..1119 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:25855297" FT REPEAT 62..92 FT /note="ANK 1" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 97..126 FT /note="ANK 2" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 130..160 FT /note="ANK 3" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 164..193 FT /note="ANK 4" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 197..226 FT /note="ANK 5" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 238..267 FT /note="ANK 6" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 271..301 FT /note="ANK 7" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 308..337 FT /note="ANK 8" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 341..370 FT /note="ANK 9" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 374..403 FT /note="ANK 10" FT /evidence="ECO:0000305|PubMed:25855297" FT REPEAT 412..441 FT /note="ANK 11" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 445..474 FT /note="ANK 12" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 481..510 FT /note="ANK 13" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 513..542 FT /note="ANK 14" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 547..576 FT /note="ANK 15" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT REPEAT 579..609 FT /note="ANK 16" FT /evidence="ECO:0000255, ECO:0000305|PubMed:25855297" FT COILED 1042..1071 FT /evidence="ECO:0000305|PubMed:25855297" FT BINDING 414 FT /ligand="(E)-cinnamaldehyde" FT /ligand_id="ChEBI:CHEBI:16731" FT /ligand_note="agonist" FT /note="covalent" FT /evidence="ECO:0000250|UniProtKB:Q8BLA8" FT BINDING 421 FT /ligand="(E)-cinnamaldehyde" FT /ligand_id="ChEBI:CHEBI:16731" FT /ligand_note="agonist" FT /note="covalent" FT /evidence="ECO:0000250|UniProtKB:Q8BLA8" FT BINDING 621 FT /ligand="(E)-cinnamaldehyde" FT /ligand_id="ChEBI:CHEBI:16731" FT /ligand_note="agonist" FT /note="covalent; Cys highly reactive" FT /evidence="ECO:0000250|UniProtKB:Q8BLA8, FT ECO:0000305|PubMed:17164327, ECO:0000305|PubMed:27241698" FT BINDING 641 FT /ligand="(E)-cinnamaldehyde" FT /ligand_id="ChEBI:CHEBI:16731" FT /ligand_note="agonist" FT /note="covalent" FT /evidence="ECO:0000305|PubMed:17164327" FT BINDING 665 FT /ligand="(E)-cinnamaldehyde" FT /ligand_id="ChEBI:CHEBI:16731" FT /ligand_note="agonist" FT /note="covalent" FT /evidence="ECO:0000305|PubMed:17164327, FT ECO:0000305|PubMed:27241698" FT BINDING 710 FT /ligand="(E)-cinnamaldehyde" FT /ligand_id="ChEBI:CHEBI:16731" FT /ligand_note="agonist" FT /note="covalent" FT /evidence="ECO:0000305|PubMed:17164327" FT BINDING 1046..1052 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo- FT inositol)" FT /ligand_id="ChEBI:CHEBI:57880" FT /evidence="ECO:0000305|PubMed:25855297" FT SITE 620 FT /note="Required for C-621 reactivity" FT /evidence="ECO:0000269|PubMed:27241698" FT SITE 622 FT /note="Key residue for activation by the scorpion wasabi FT receptor toxin" FT /evidence="ECO:0000269|PubMed:31447178" FT SITE 634 FT /note="Important residue for activation by the scorpion FT wasabi receptor toxin" FT /evidence="ECO:0000269|PubMed:31447178" FT SITE 646 FT /note="Important residue for activation by the scorpion FT wasabi receptor toxin" FT /evidence="ECO:0000269|PubMed:31447178" FT MOD_RES 394 FT /note="4-hydroxyproline; by EGLN1; transient; in normoxia FT and hyperoxia" FT /evidence="ECO:0000269|PubMed:21873995" FT MOD_RES 633 FT /note="Cysteine sulfenic acid (-SOH); transient; in FT hyperoxia" FT /evidence="ECO:0000305|PubMed:21873995" FT MOD_RES 856 FT /note="Cysteine sulfenic acid (-SOH); transient; in FT hyperoxia" FT /evidence="ECO:0000305|PubMed:21873995" FT CARBOHYD 747 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 753 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 192..665 FT /note="Alternate" FT /evidence="ECO:0000250|UniProtKB:Q8BLA8" FT DISULFID 462..665 FT /note="Alternate" FT /evidence="ECO:0000250|UniProtKB:Q8BLA8" FT DISULFID 608..621 FT /note="Alternate" FT /evidence="ECO:0000250|UniProtKB:Q8BLA8" FT DISULFID 621..665 FT /note="Alternate" FT /evidence="ECO:0000250|UniProtKB:Q8BLA8" FT DISULFID 633..856 FT /note="Alternate; transient; in hyperoxia; unknown whether FT inter- or intrachain" FT /evidence="ECO:0000305|PubMed:21873995" FT VARIANT 3 FT /note="R -> C (in dbSNP:rs13268757)" FT /evidence="ECO:0000269|PubMed:10066796" FT /id="VAR_020660" FT VARIANT 58 FT /note="R -> T (in dbSNP:rs16937976)" FT /evidence="ECO:0000269|PubMed:10066796" FT /id="VAR_047471" FT VARIANT 179 FT /note="E -> K (in dbSNP:rs920829)" FT /id="VAR_020661" FT VARIANT 186 FT /note="K -> N (in dbSNP:rs7819749)" FT /evidence="ECO:0000269|PubMed:10066796" FT /id="VAR_020662" FT VARIANT 855 FT /note="N -> S (in FEPS1; 5-fold increase in inward current FT when stimulated by the agonist cinnamaldehyde compared to FT wild-type at normal neuronal resting potential; consistent FT with a gain of function mutation; dbSNP:rs398123010)" FT /evidence="ECO:0000269|PubMed:20547126" FT /id="VAR_069737" FT VARIANT 1018 FT /note="H -> R (in dbSNP:rs959976)" FT /id="VAR_020663" FT MUTAGEN 173 FT /note="C->S: Decrease in activation by hyperoxia and FT diallyl disulfide." FT /evidence="ECO:0000269|PubMed:21873995" FT MUTAGEN 192 FT /note="C->S: Decrease in activation by hyperoxia and FT diallyl disulfide." FT /evidence="ECO:0000269|PubMed:21873995" FT MUTAGEN 394 FT /note="P->A: Loss of answer to hypoxia and hydroxylase FT inhibitor DMOG, but not to AITC and hyperoxia." FT /evidence="ECO:0000269|PubMed:21873995" FT MUTAGEN 620 FT /note="K->A: Important decrease in electrophile-evoked FT response." FT /evidence="ECO:0000269|PubMed:27241698" FT MUTAGEN 621 FT /note="C->A,S: Decrease in electrophile-evoked response. No FT change in answer to hyperoxia and diallyl disulfide. In FT TRPA1-3C-K708R/Q; loss in irritant-evoked response." FT /evidence="ECO:0000269|PubMed:17164327, FT ECO:0000269|PubMed:21873995, ECO:0000269|PubMed:27241698, FT ECO:0000269|PubMed:30878828" FT MUTAGEN 622 FT /note="P->A: Loss of activation by the scorpion wasabi FT receptor toxin." FT /evidence="ECO:0000269|PubMed:31447178" FT MUTAGEN 633 FT /note="C->S: Decrease in activation by hyperoxia and FT diallyl disulfide. Important decrease in activation by FT hyperoxia and diallyl disulfide; when associated with FT S-856." FT /evidence="ECO:0000269|PubMed:21873995" FT MUTAGEN 634 FT /note="M->L: Loss of activation by the scorpion wasabi FT receptor toxin." FT /evidence="ECO:0000269|PubMed:31447178" FT MUTAGEN 641 FT /note="C->A,S: Decrease in electrophile-evoked and FT hyperoxia response. In TRPA1-3C-K708R/Q; loss in FT irritant-evoked response." FT /evidence="ECO:0000269|PubMed:17164327, FT ECO:0000269|PubMed:21873995" FT MUTAGEN 646 FT /note="T->P: Loss of activation by the scorpion wasabi FT receptor toxin." FT /evidence="ECO:0000269|PubMed:31447178" FT MUTAGEN 665 FT /note="C->A,L,S: Decrease in electrophile-evoked and FT hyperoxia response. In TRPA1-3C-K708R/Q; loss in FT irritant-evoked response." FT /evidence="ECO:0000269|PubMed:17164327, FT ECO:0000269|PubMed:21873995, ECO:0000269|PubMed:27241698" FT MUTAGEN 710 FT /note="K->R,Q: No change in electrophile sensitivity. In FT TRPA1-3C-K708R/Q; loss in irritant-evoked response." FT MUTAGEN 856 FT /note="C->S: Decrease in activation by hyperoxia and FT diallyl disulfide. Important decrease in activation by FT hyperoxia and diallyl disulfide; when associated with FT S-633." FT /evidence="ECO:0000269|PubMed:21873995" FT MUTAGEN 909 FT /note="F->A,T: Loss of inhibition by A-967079, AP-18, and FT ASD. Increase in activation by cinnamaldehyde, AITC and FT acrolein." FT /evidence="ECO:0000269|PubMed:25855297, FT ECO:0000269|PubMed:30878828" FT MUTAGEN 944 FT /note="F->A: Loss of inhibition by A-967079, AP-18, and FT ASD. Weak or no change in activation by cinnamaldehyde, FT AITC and acrolein." FT /evidence="ECO:0000269|PubMed:30878828" FT HELIX 325..329 FT /evidence="ECO:0007829|PDB:6HC8" FT HELIX 448..455 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 459..466 FT /evidence="ECO:0007829|PDB:6V9V" FT TURN 473..475 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 485..491 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 495..504 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 512..514 FT /evidence="ECO:0007829|PDB:6V9W" FT HELIX 517..522 FT /evidence="ECO:0007829|PDB:6V9V" FT TURN 523..525 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 527..533 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 538..540 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 551..557 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 561..569 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 578..580 FT /evidence="ECO:0007829|PDB:6V9X" FT HELIX 583..589 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 593..601 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 602..604 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 605..609 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 617..619 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 622..628 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 631..641 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 642..647 FT /evidence="ECO:0007829|PDB:7OR0" FT STRAND 650..653 FT /evidence="ECO:0007829|PDB:6PQP" FT STRAND 656..659 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 661..663 FT /evidence="ECO:0007829|PDB:6V9V" FT TURN 668..670 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 673..676 FT /evidence="ECO:0007829|PDB:6PQP" FT HELIX 684..691 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 695..698 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 701..713 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 715..739 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 742..744 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 745..747 FT /evidence="ECO:0007829|PDB:7OR0" FT STRAND 750..753 FT /evidence="ECO:0007829|PDB:7OR0" FT STRAND 761..763 FT /evidence="ECO:0007829|PDB:7OR0" FT HELIX 767..794 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 795..799 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 804..818 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 820..822 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 828..849 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 851..856 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 857..871 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 874..891 FT /evidence="ECO:0007829|PDB:6V9V" FT TURN 892..894 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 898..900 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 901..910 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 911..913 FT /evidence="ECO:0007829|PDB:6V9V" FT TURN 919..922 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 923..927 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 934..947 FT /evidence="ECO:0007829|PDB:6V9V" FT TURN 948..950 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 951..969 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 971..989 FT /evidence="ECO:0007829|PDB:6V9V" FT HELIX 992..998 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 1001..1005 FT /evidence="ECO:0007829|PDB:6V9V" FT STRAND 1007..1009 FT /evidence="ECO:0007829|PDB:6PQQ" FT HELIX 1016..1024 FT /evidence="ECO:0007829|PDB:6PQQ" FT HELIX 1041..1070 FT /evidence="ECO:0007829|PDB:6V9V" SQ SEQUENCE 1119 AA; 127501 MW; 283BF31BC77CF71B CRC64; MKRSLRKMWR PGEKKEPQGV VYEDVPDDTE DFKESLKVVF EGSAYGLQNF NKQKKLKRCD DMDTFFLHYA AAEGQIELME KITRDSSLEV LHEMDDYGNT PLHCAVEKNQ IESVKFLLSR GANPNLRNFN MMAPLHIAVQ GMNNEVMKVL LEHRTIDVNL EGENGNTAVI IACTTNNSEA LQILLKKGAK PCKSNKWGCF PIHQAAFSGS KECMEIILRF GEEHGYSRQL HINFMNNGKA TPLHLAVQNG DLEMIKMCLD NGAQIDPVEK GRCTAIHFAA TQGATEIVKL MISSYSGSVD IVNTTDGCHE TMLHRASLFD HHELADYLIS VGADINKIDS EGRSPLILAT ASASWNIVNL LLSKGAQVDI KDNFGRNFLH LTVQQPYGLK NLRPEFMQMQ QIKELVMDED NDGCTPLHYA CRQGGPGSVN NLLGFNVSIH SKSKDKKSPL HFAASYGRIN TCQRLLQDIS DTRLLNEGDL HGMTPLHLAA KNGHDKVVQL LLKKGALFLS DHNGWTALHH ASMGGYTQTM KVILDTNLKC TDRLDEDGNT ALHFAAREGH AKAVALLLSH NADIVLNKQQ ASFLHLALHN KRKEVVLTII RSKRWDECLK IFSHNSPGNK CPITEMIEYL PECMKVLLDF CMLHSTEDKS CRDYYIEYNF KYLQCPLEFT KKTPTQDVIY EPLTALNAMV QNNRIELLNH PVCKEYLLMK WLAYGFRAHM MNLGSYCLGL IPMTILVVNI KPGMAFNSTG IINETSDHSE ILDTTNSYLI KTCMILVFLS SIFGYCKEAG QIFQQKRNYF MDISNVLEWI IYTTGIIFVL PLFVEIPAHL QWQCGAIAVY FYWMNFLLYL QRFENCGIFI VMLEVILKTL LRSTVVFIFL LLAFGLSFYI LLNLQDPFSS PLLSIIQTFS MMLGDINYRE SFLEPYLRNE LAHPVLSFAQ LVSFTIFVPI VLMNLLIGLA VGDIAEVQKH ASLKRIAMQV ELHTSLEKKL PLWFLRKVDQ KSTIVYPNKP RSGGMLFHIF CFLFCTGEIR QEIPNADKSL EMEILKQKYR LKDLTFLLEK QHELIKLIIQ KMEIISETED DDSHCSFQDR FKKEQMEQRN SRWNTVLRAV KAKTHHLEP //