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|Mutation Type||critical splice donor site (2 bp from exon)|
|Coordinate||14,891,303 bp (GRCm38)|
|Base Change||A ⇒ G (forward strand)|
|Gene Name||transient receptor potential cation channel, subfamily A, member 1|
|Chromosomal Location||14,872,648-14,918,862 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The structure of the protein encoded by this gene is highly related to both the protein ankyrin and transmembrane proteins. The specific function of this protein has not yet been determined; however, studies indicate the function may involve a role in signal transduction and growth control. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mutations in this gene result in altered nociception and neuron responses to isothiocyanate or thiosulfinate compounds like those found in mustard oil and garlic. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000043594]|
|Predicted Effect||probably null|
|Phenotypic Category||Autosomal Recessive|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2018-07-19 10:00 AM by Anne Murray|
|Record Created||2015-11-19 4:40 PM|
The fear-2 phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R1035, some of which showed reduced innate fear/defensive behaviors compared to wild-type littermates after exposure to predator odor 2,4,5-trimethyl-3-thiazoline (TMT) and its potent analog 2-methyl-2-thiazoline (2MT) (1) (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 31 mutations. The reduced innate fear phenotype was linked by continuous variable mapping to a mutation in Trpa1: a T to C transition at base pair 14,891,303 (v38) on chromosome 1, or base pair 27,712 in the GenBank genomic region NC_000067 within the donor splice site of intron 15 (1). Linkage was found with a recessive model of inheritance to the fear response, wherein four variant homozygotes departed phenotypically from seven homozygous reference mice and six heterozygous mice with a P value of 2.134 x 10-11 (Figure 2).
The effect of the mutation at the cDNA and protein level have not examined, but the mutation is predicted to result in skipping of the 94-nucleotide exon 15 (out of 27 total exons), resulting in a frame-shifted protein product beginning after amino acid 605, and termination after the inclusion of two aberrant amino acids.
Genomic numbering corresponds to NC_000067. The donor splice site of intron 15, which is destroyed by the fear-2 mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
Transient receptor potential ankyrin 1 (TRPA1; alternatively, ANKTM1) is one of 28 members of the mammalian transient receptor potential (TRP) channel superfamily. The TRP channels can be subdivided into six subfamilies: TRP Canonical (TRPC), TRP Melastatin (TRPM), TRP Ankyrin (TRPA), TRP Mucolipin (TRPML), TRP Polycystin (TRPP), and TRP Vanilloid (TRPV). Mammals do not have a representative of the seventh TRP subfamily, TRPN (no mechanoreceptor potential C [nompC] TRP). TRPA1 is the only member of the TRPA family.
The TRP proteins have large intracellular N- and C-terminal tails as well as six transmembrane (TM)-spanning domains, with a putative hydrophobic, pore-forming region between the fifth and sixth domains. The TRP proteins have variable combinations of other domains within the cytoplasmic regions, including ankyrin repeats, coiled-coil regions, a NUDIX domain, an EF hand Ca2 +-binding motif, a CIRB motif, a PDZ motif, and a TRP box [reviewed in (2)].
The N-terminal tail of TRPA1 is 721 amino acids in length and contains 14 ankyrin repeats (Figure 3). TRPA1 also has three EF hands within the N-terminal tail that mediate channel activation in response to increased levels of intracellular calcium (3). The ankyrin repeat domain (ARD) is proposed to mediate trafficking of TRPA1 to the plasma membrane or plasma membrane insertion (4). In addition, ARDs facilitate protein-protein interactions. The ARD is proposed to function in the regulation of gating and integration of multiple stimuli. Three point mutations affecting the sixth ankyrin repeat of mouse TRPA1 makes the protein warm activated (5). The chemical sensitivity of the mutant channel was not affected.
Single-particle electron cryo-microscopy has been used to determine the structure of full-length human TRPA1 [Figure 4; PDB: 3J9P; (6)]. TRPA1 has a “TRP-like” domain in the C-terminal tail (6). The TRP domain is a short hydrophobic segment that is necessary for phosphatidylinositol 4,5-bisphosphate (PIP2) binding. PIP2 is a ubiquitously expressed phospholipid and regulator of channel function. Within the C-terminus is a coiled-coil that mediates subunit interactions.
Four pore-forming TRP subunits assemble as homo- or heterotetramers to comprise a TRP channel. In addition to forming a homotetramer, TRPA1 can form a heterotetrameric complex with TRPV1 in vitro (7). TRPA1 is proposed to form four disulfide bonds within the N-terminus. Cys619, Cys639, and Cys663 are conserved cysteines within the linker region between the ARD and the first transmembrane domain.
Gly878 in mouse and rat TM5 is proposed to mediate the cold sensing property of the mouse and rat TRPA1. TM5 is also a determinant of menthol sensitivity in mammalian TRPA1 channels (8). Mutation of Gly878 to valine, similar to what is found in human and monkey TRPA1 (Val875), resulted in loss of cold sensitivity in rat TRPA1 (9).
TRPA1 is expressed in the cerebellum, hippocampus, and forebrain (10) as well as in primary sensory neurons of the trigeminal, dorsal root, and nodose ganglia (11). TRPA1 is predominantly expressed in small-diameter, unmyelinated and partially myelinated C- and Aδ-fibers in the periphery. TRPA1 is also expressed in airway and lung epithelial and smooth muscle cells (12), peptidergic sensory neurons (13), enterochromaffin cells in the gastrointestinal tract (14;15), pancreas (16), the inner ear (17), skin (14), dental pulp (18), vascular endothelia, and airway epithelial cells (12;17).
The TRPV, TRPM, and TPRA subfamilies function in the sensory detection transduction of nociception and pain. The TRP channels respond to several external stimuli such as light (i.e. phototransduction), chemicals, and temperature as well as mechanical and osmotic pressures (19-23). TRP channels have roles in diverse processes including olfaction, nociception, speech, regulation of blood circulation, pain signal transduction, gut motility, mineral absorption, fluid balance epithelial Ca2+ transport, development of airway and bladder hypersensitivities, cell survival, growth, and death (19).
The TRP channels function by facilitating the transmembrane flow of cations (i.e. Na+ and Ca2+) down electrochemical gradients to depolarize the cell as well as to mediate signal transduction (24;25). TRP channels can be activated through the activation of phospholipase C (PLC) by G protein-coupled receptors and receptor tyrosine kinases. Activation of PLC leads to hydrolysis of PIP2, producing diacylglycerol (DAG) and inositol (1,4,5) triphosphate (IP3) (Figure 5). PIP2 hydrolysis and DAG production modulate TRP channel activity. The TRP channels can also be activated by exogenous small organic molecules (e.g. capsaicin), endogenous lipids, purine nucleotides and their metabolites (e.g. adenosine diphosphoribose (ADP-ribose)), and inorganic ions (e.g. Ca2+ and Mg2+) (25). TRP channels can also be directly activated by temperature changes, mechanical stimuli, coupling to IP3 receptors, cell swelling, channel phosphorylation through protein kinases A, C, and G (PKA, PKC, and PKG, respectively), and Ca2+/calmodulin signaling (25). The function of TRP channels as “store-operated calcium entry” channels activated by IP3-mediated release of intracellular Ca2+ stores is controversial (25).
TRPA1 is activated by several stimulants, including allyl isothiocyanate (AITC; a compound in horseradish, wasabi, and mustard), allicin and diallyl disulfide (in raw garlic), cinnamaldehyde (in cinnamon), gingerol (in ginger), thymol (in thyme), eugenol (in cloves), and carvacrol (in oregano), and acrolein and tear gas (environmental irritants). TRPA1 can also be activated by endogenous stimulants and inflammatory proteins, including reactive oxygen, nitrogen, and carbonyl species, hydrogen peroxide, peroxynitrite, and 4-hydroxynonenal (26;27). TRPA1 activation by inflammatory proteins facilitates the transduction of nociceptive signals related to tissue damage and inflammation. After injury, the cyclooxygenase pathway leads to the production of prostaglandins. The prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) activates dissociated dorsal root ganglion cells (28).
The role of TRPA1 in sensing cold temperatures is controversial; however, the role of TRPA1 in mediating cold hypersensitivity in models of neuropathic pain has been shown (26). While primate TRPA1 can be activated by cold temperatures, rodent TRPA1 is insensitive to cold temperatures. The differences between the studies have been attributed to differences in experimental conditions (e.g., expression system and expression level). Also, the differences may be due to species-specific properties of TRPA1. In a study that performed a side-by-side comparison of mouse, rat, human, and monkey TRPA1 under identical conditions determined that all four TRPA1s were potentiated by AITC, while cold only activated the mouse and rat orthologs. The primate TRPA1s were insensitive to temperature changes.
TRPA1 is associated with bradykinin B2 and prostaglandin EP3 receptor-associated signaling (29). When TRPA1 was coexpressed with the bradykinin receptor and the M1 muscarinic acetylcholine receptor, a dramatic increase in the magnitude of the signal was observed compared to when the proteins were expressed alone.
In humans, patients with elevated pain sensitivity exhibit differential DNA methylation in the vicinity of the TRPA1 gene, indicating that this may be a contributing factor in individual differences in pain sensitivity (30). A gain-of-function mutation in TRPA1 (N855S) is linked to familial episodic pain syndrome (FEPS; OMIM: #615040) (31). FEPS is an autosomal dominant neurological disorder characterized by early-onset of episodic upper body pain triggered by fatigue, fasting, cold, illness, and/or physical exertion (31). The pain episodes also included breathing difficulties, tachycardia, sweating, generalized pallor, peribuccal cyanosis, and stiffness of the abdominal wall. The patients did not report altered pain sensitivity outside of the episodes.
TRPA1 functions in several inflammatory conditions, including allergic contact dermatitis (32). The activation of TRPA1-expressing nerve fibers in the lung promotes neurogenic inflammation, subsequently contributing to airway constriction and cough in patients with asthma and other respiratory disorders (33;34). TRPA1 functions in conditions of chronic itch whereby it is involved in the transduction of the itching sensation as well as in the changes that occur in the skin associated with chronic itch (35).
Trpa1-deficient (Trpa1-/-) mice exhibit behavioral deficits in response to mechanical stimulation, AITC, and cold temperatures (36). Two independent knockout mouse models were generated and characterized. One model was reported to not have menthol-insensitive, cold-activated trigeminal neurons (37). In addition, this model was comparable to wild-type mice in the latency to lift the paw in cold plate assays, flinching in acetone-induced cooling of the paw, and in temperature preference assay (37). Bautista et al. concluded that TRPA1 does not behave as a cold sensor. In the second TRPA1 knockout model, the mice exhibited reduced paw lifting upon exposure to a cold plate as well as reduced responses to acetone application compared to wild-type mice ((36).
TRPA1 acts as a chemosensor for 2MT/TMT (1). Trpa1−/− mice displayed diminished freezing response to 2MT or TMT as compared to wild-type and heterozygous littermates (Figure 6) (1). 2MT-evoked c-fos induction was reduced in the CeA, vPAG, and the paraventricular nucleus (PVN) of the hypothalamus in Trpa1−/− brains relative to that in Trpa1+/− brains (Figure 7).
fear-2(F):5'- TCCCTACTTTCTGAGGAGGCAGTC -3'
fear-2(R):5'- TGACCAGCAATGCCAAGCAGTG -3'
fear-2_seq(F):5'- TGTGAAGAGCATTCATTCAGC -3'
fear-2_seq(R):5'- CTCCAAGCAATCGATGTCCAATC -3'
1. Wang, Y., Cao, L., Lee, C. Y., Matsuo, T., Wu, K., Asher, G., Tang, L., Saitoh, T., Russell, J., Klewe-Nebenius, D., Wang, L., Soya, S., Hasegawa, E., Cherasse, Y., Zhou, J., Li, Y., Wang, T., Zhan, X., Miyoshi, C., Irukayama, Y., Cao, J., Meeks, J. P., Gautron, L., Wang, Z., Sakurai, K., Funato, H., Sakurai, T., Yanagisawa, M., Nagase, H., Kobayakawa, R., Kobayakawa, K., Beutler, B., and Liu, Q. (2018) Large-Scale Forward Genetics Screening Identifies Trpa1 as a Chemosensor for Predator Odor-Evoked Innate Fear Behaviors. Nat Commun. 9, 2041-018-04324-3.
2. Benemei, S., Patacchini, R., Trevisani, M., and Geppetti, P. (2015) TRP Channels. Curr Opin Pharmacol. 22, 18-23.
3. Wang, L., Cvetkov, T. L., Chance, M. R., and Moiseenkova-Bell, V. Y. (2012) Identification of in Vivo Disulfide Conformation of TRPA1 Ion Channel. J Biol Chem. 287, 6169-6176.
4. Nilius, B., Prenen, J., and Owsianik, G. (2011) Irritating Channels: The Case of TRPA1. J Physiol. 589, 1543-1549.
5. Jabba, S., Goyal, R., Sosa-Pagan, J. O., Moldenhauer, H., Wu, J., Kalmeta, B., Bandell, M., Latorre, R., Patapoutian, A., and Grandl, J. (2014) Directionality of Temperature Activation in Mouse TRPA1 Ion Channel can be Inverted by Single-Point Mutations in Ankyrin Repeat Six. Neuron. 82, 1017-1031.
6. Paulsen, C. E., Armache, J. P., Gao, Y., Cheng, Y., and Julius, D. (2015) Structure of the TRPA1 Ion Channel Suggests Regulatory Mechanisms. Nature. 520, 511-517.
7. Fischer, M. J., Balasuriya, D., Jeggle, P., Goetze, T. A., McNaughton, P. A., Reeh, P. W., and Edwardson, J. M. (2014) Direct Evidence for Functional TRPV1/TRPA1 Heteromers. Pflugers Arch. 466, 2229-2241.
8. Xiao, B., Dubin, A. E., Bursulaya, B., Viswanath, V., Jegla, T. J., and Patapoutian, A. (2008) Identification of Transmembrane Domain 5 as a Critical Molecular Determinant of Menthol Sensitivity in Mammalian TRPA1 Channels. J Neurosci. 28, 9640-9651.
9. Chen, J., Kang, D., Xu, J., Lake, M., Hogan, J. O., Sun, C., Walter, K., Yao, B., and Kim, D. (2013) Species Differences and Molecular Determinant of TRPA1 Cold Sensitivity. Nat Commun. 4, 2501.
10. Fernandes, E. S., Fernandes, M. A., and Keeble, J. E. (2012) The Functions of TRPA1 and TRPV1: Moving Away from Sensory Nerves. Br J Pharmacol. 166, 510-521.
11. Story, G. M., Peier, A. M., Reeve, A. J., Eid, S. R., Mosbacher, J., Hricik, T. R., Earley, T. J., Hergarden, A. C., Andersson, D. A., Hwang, S. W., McIntyre, P., Jegla, T., Bevan, S., and Patapoutian, A. (2003) ANKTM1, a TRP-Like Channel Expressed in Nociceptive Neurons, is Activated by Cold Temperatures. Cell. 112, 819-829.
12. Nassini, R., Pedretti, P., Moretto, N., Fusi, C., Carnini, C., Facchinetti, F., Viscomi, A. R., Pisano, A. R., Stokesberry, S., Brunmark, C., Svitacheva, N., McGarvey, L., Patacchini, R., Damholt, A. B., Geppetti, P., and Materazzi, S. (2012) Transient Receptor Potential Ankyrin 1 Channel Localized to Non-Neuronal Airway Cells Promotes Non-Neurogenic Inflammation. PLoS One. 7, e42454.
13. Benemei, S., Fusi, C., Trevisan, G., and Geppetti, P. (2014) The TRPA1 Channel in Migraine Mechanism and Treatment. Br J Pharmacol. 171, 2552-2567.
14. Atoyan, R., Shander, D., and Botchkareva, N. V. (2009) Non-Neuronal Expression of Transient Receptor Potential Type A1 (TRPA1) in Human Skin. J Invest Dermatol. 129, 2312-2315.
15. Engel, M. A., Leffler, A., Niedermirtl, F., Babes, A., Zimmermann, K., Filipovic, M. R., Izydorczyk, I., Eberhardt, M., Kichko, T. I., Mueller-Tribbensee, S. M., Khalil, M., Siklosi, N., Nau, C., Ivanovic-Burmazovic, I., Neuhuber, W. L., Becker, C., Neurath, M. F., and Reeh, P. W. (2011) TRPA1 and Substance P Mediate Colitis in Mice. Gastroenterology. 141, 1346-1358.
16. Shigetomi, E., Tong, X., Kwan, K. Y., Corey, D. P., and Khakh, B. S. (2011) TRPA1 Channels Regulate Astrocyte Resting Calcium and Inhibitory Synapse Efficacy through GAT-3. Nat Neurosci. 15, 70-80.
17. Pozsgai, G., Bodkin, J. V., Graepel, R., Bevan, S., Andersson, D. A., and Brain, S. D. (2010) Evidence for the Pathophysiological Relevance of TRPA1 Receptors in the Cardiovascular System in Vivo. Cardiovasc Res. 87, 760-768.
18. Cao, D. S., Zhong, L., Hsieh, T. H., Abooj, M., Bishnoi, M., Hughes, L., and Premkumar, L. S. (2012) Expression of Transient Receptor Potential Ankyrin 1 (TRPA1) and its Role in Insulin Release from Rat Pancreatic Beta Cells. PLoS One. 7, e38005.
19. Alawi, K., and Keeble, J. (2010) The Paradoxical Role of the Transient Receptor Potential Vanilloid 1 Receptor in Inflammation. Pharmacol Ther. 125, 181-195.
20. van de Graaf, S. F., Rescher, U., Hoenderop, J. G., Verkaart, S., Bindels, R. J., and Gerke, V. (2008) TRPV5 is Internalized Via Clathrin-Dependent Endocytosis to Enter a Ca2+-Controlled Recycling Pathway. J Biol Chem. 283, 4077-4086.
21. Holzer, P. (2011) Transient Receptor Potential (TRP) Channels as Drug Targets for Diseases of the Digestive System. Pharmacol Ther. 131, 142-170.
23. Hoenderop, J. G., Voets, T., Hoefs, S., Weidema, F., Prenen, J., Nilius, B., and Bindels, R. J. (2003) Homo- and Heterotetrameric Architecture of the Epithelial Ca2+ Channels TRPV5 and TRPV6. EMBO J. 22, 776-785.
24. Vesey, D. A. (2010) Transport Pathways for Cadmium in the Intestine and Kidney Proximal Tubule: Focus on the Interaction with Essential Metals. Toxicol Lett. 198, 13-19.
25. Ramsey, I. S., Delling, M., and Clapham, D. E. (2006) An Introduction to TRP Channels. Annu Rev Physiol. 68, 619-647.
26. Nassini, R., Materazzi, S., Benemei, S., and Geppetti, P. (2014) The TRPA1 Channel in Inflammatory and Neuropathic Pain and Migraine. Rev Physiol Biochem Pharmacol. 167, 1-43.
28. Takahashi, N., Mizuno, Y., Kozai, D., Yamamoto, S., Kiyonaka, S., Shibata, T., Uchida, K., and Mori, Y. (2008) Molecular Characterization of TRPA1 Channel Activation by Cysteine-Reactive Inflammatory Mediators. Channels (Austin). 2, 287-298.
29. Grace, M., Birrell, M. A., Dubuis, E., Maher, S. A., and Belvisi, M. G. (2012) Transient Receptor Potential Channels Mediate the Tussive Response to Prostaglandin E2 and Bradykinin. Thorax. 67, 891-900.
30. Bell, J. T., Loomis, A. K., Butcher, L. M., Gao, F., Zhang, B., Hyde, C. L., Sun, J., Wu, H., Ward, K., Harris, J., Scollen, S., Davies, M. N., Schalkwyk, L. C., Mill, J., MuTHER Consortium, Williams, F. M., Li, N., Deloukas, P., Beck, S., McMahon, S. B., Wang, J., John, S. L., and Spector, T. D. (2014) Differential Methylation of the TRPA1 Promoter in Pain Sensitivity. Nat Commun. 5, 2978.
31. Kremeyer, B., Lopera, F., Cox, J. J., Momin, A., Rugiero, F., Marsh, S., Woods, C. G., Jones, N. G., Paterson, K. J., Fricker, F. R., Villegas, A., Acosta, N., Pineda-Trujillo, N. G., Ramirez, J. D., Zea, J., Burley, M. W., Bedoya, G., Bennett, D. L., Wood, J. N., and Ruiz-Linares, A. (2010) A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome. Neuron. 66, 671-680.
32. Liu, B., Escalera, J., Balakrishna, S., Fan, L., Caceres, A. I., Robinson, E., Sui, A., McKay, M. C., McAlexander, M. A., Herrick, C. A., and Jordt, S. E. (2013) TRPA1 Controls Inflammation and Pruritogen Responses in Allergic Contact Dermatitis. FASEB J. 27, 3549-3563.
33. Andre, E., Campi, B., Materazzi, S., Trevisani, M., Amadesi, S., Massi, D., Creminon, C., Vaksman, N., Nassini, R., Civelli, M., Baraldi, P. G., Poole, D. P., Bunnett, N. W., Geppetti, P., and Patacchini, R. (2008) Cigarette Smoke-Induced Neurogenic Inflammation is Mediated by Alpha,Beta-Unsaturated Aldehydes and the TRPA1 Receptor in Rodents. J Clin Invest. 118, 2574-2582.
34. Bessac, B. F., Sivula, M., von Hehn, C. A., Escalera, J., Cohn, L., and Jordt, S. E. (2008) TRPA1 is a Major Oxidant Sensor in Murine Airway Sensory Neurons. J Clin Invest. 118, 1899-1910.
35. Wilson, S. R., Nelson, A. M., Batia, L., Morita, T., Estandian, D., Owens, D. M., Lumpkin, E. A., and Bautista, D. M. (2013) The Ion Channel TRPA1 is Required for Chronic Itch. J Neurosci. 33, 9283-9294.
36. Kwan, K. Y., Allchorne, A. J., Vollrath, M. A., Christensen, A. P., Zhang, D. S., Woolf, C. J., and Corey, D. P. (2006) TRPA1 Contributes to Cold, Mechanical, and Chemical Nociception but is Not Essential for Hair-Cell Transduction. Neuron. 50, 277-289.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Qinghua Liu and Bruce Beutler|
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