Alternative titles; symbols
HGNC Approved Gene Symbol: TRPA1
Cytogenetic location: 8q21.11 Genomic coordinates (GRCh38) : 8:72,021,250-72,090,010 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q21.11 | ?Episodic pain syndrome, familial, 1 | 615040 | Autosomal dominant | 3 |
The TRPA1 gene encodes a cation channel expressed in primary afferent nociceptors (summary by Kremeyer et al., 2010).
A set of transformation-sensitive proteins expressed by normal fibroblasts but specifically repressed after oncogenic transformation has emerged from studies of tumor virus-transformed fibroblasts. To identify proteins lost during the establishment of the transformed phenotype of a tumor cell, Schenker and Trueb (1998) prepared a subtracted cDNA library with mRNA from normal human fibroblasts and from their matched SV40-transformed counterparts. They identified more than 40 clones that showed a dramatic reduction in their relative expression after oncogenic transformation, including a partial cDNA encoding a novel ankyrin-like protein, which has been named ANKTM1. ANKTM1 gene expression was consistently downregulated in a variety of cell lines derived from spontaneous mesenchymal tumors.
By screening a human lung fibroblast cDNA library with the partial ANKTM1 cDNA, followed by 5-prime RACE, Jaquemar et al. (1999) isolated the complete ANKTM1 coding sequence. The deduced 1,119-amino acid ANKTM1 protein has a calculated molecular mass of 127.4 kD; the authors called it p120. ANKTM1 protein from fibroblast and liposarcoma cell extracts migrated as a 130-kD polypeptide on Western blots. The predicted ANKTM1 protein can be divided into 2 parts, an N-terminal portion that is related to the cytoskeletal protein ankyrin (ANK1; 612641) and a C-terminal portion that is related to transmembrane proteins. The N-terminal region contains eighteen 33-amino acid repeats, 15 of which share 21 to 52% sequence identity with the consensus motif derived from the repeats of ankyrin-like proteins and 3 of which share only partial similarity with the consensus repeat sequence. The C-terminal region contains 7 hydrophobic segments, 6 of which are putative transmembrane domains and 1 of which may enter the lipid bilayer only partially, possibly as a pore loop structure. ANKTM1 is predicted to assume a type II membrane orientation, with the N terminus located cytoplasmically. The overall structure of ANKTM1 is reminiscent of TRP-like proteins (e.g., TRPC7; 603749), which function as store-operated calcium channels. ANKTM1 contains 5 potential N-glycosylation sites, but 3 are situated cytoplasmically and are unlikely to be used. ANKTM1 does not contain an N-terminal signal peptide. Northern blot analysis detected a 4.6-kb ANKTM1 transcript in human fibroblasts. ANKTM1 expression was not observed in SV40-transformed fibroblasts or in cell lines derived from the following spontaneous mesenchymal tumors: 4 rhabdomyosarcomas, 2 fibrosarcomas, 1 osteosarcoma, and 1 chondrosarcoma. ANKTM1 was expressed in cells from a liposarcoma and in 1 of 2 leiomyosarcoma cell lines. Northern blot analysis did not detect ANKTM1 expression in any of several adult or fetal human tissues. However, RT-PCR of RNA from a 12-week-old human embryo showed an extremely low level of ANKTM1 expression. Overexpression of recombinant ANKTM1 protein in eukaryotic cells appeared to interfere with normal growth. Jaquemar et al. (1999) suggested that ANKTM1 may play a direct or indirect role in signal transduction and growth control.
Paulsen et al. (2015) used single-particle electron cryomicroscopy to determine the structure of full-length human TRPA1 to approximately 4-angstrom resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features were revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate cofactors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. Paulsen et al. (2015) concluded that their findings provided insights into the mechanisms of TRPA1 regulation and established a blueprint for structure-based design of analgesic and antiinflammatory agents.
Using structural and electrophyiologic analyses, Zhao et al. (2020) showed that electrophiles acted on human TRPA1 through a 2-step process in which modification of a highly reactive cysteine, cys621, promoted reorientation of a cytoplasmic loop to enhance nucleophilicity and modification of a nearby cysteine, cys665, thereby stabilizing the loop in an activating configuration. These actions modulated 2 restrictions controlling ion permeation, including widening of the selectivity filter to enhance calcium permeability and opening of a canonical gate at the cytoplasmic end of the pore. Zhao et al. (2020) proposed a model to explain functional coupling between electrophile action and these control points. They also characterized a calcium-binding pocket conserved across TRP channel subtypes that accounted for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization, and activation by metabotropic receptors.
By FISH, Jaquemar et al. (1999) mapped the TRPA1 gene to chromosome 8q13.
Gross (2021) mapped the TRPA1 gene to chromosome 8q21.11 based on an alignment of the TRPA1 sequence (GenBank NM_007332) with the genomic sequence (GRCh38).
Story et al. (2003) characterized ANKTM1, a cold-activated channel with a lower activation temperature than the cold and menthol receptor, TRPM8 (606678). ANKTM1 is a distant family member of TRP channels that shares little amino acid similarity with TRPM8. It is found in a subset of nociceptive sensory neurons where it is coexpressed with the capsaicin/heat receptor, TRPV1 (602076), but not TRPM8. Consistent with the expression of ANKTM1, the authors identified noxious cold-sensitive sensory neurons that also respond to capsaicin but not to menthol.
Jordt et al. (2004) demonstrated that mustard oil (allyl isothiocyanate) depolarizes a subpopulation of primary sensory neurons that are also activated by capsaicin, the pungent ingredient in chili peppers, and by delta-9-tetrahydrocannabinol (THC), the psychoactive component of marijuana. Both allyl isothiocyanate and THC mediate their excitatory effects by activating ANKTM1, a member of the TRP ion channel family recently implicated in the detection of noxious cold. Jordt et al. (2004) concluded that their findings identified a cellular and molecular target for the pungent action of mustard oils and supported an emerging role for TRP channels in ionotropic cannabinoid receptors.
Corey et al. (2004) suggested that TRPA1 (also known as ANKTM1) is a component of the mechanosensitive transduction channel of vertebrate hair cells. The appearance of TRPA1 mRNA expression in hair cell epithelia coincided developmentally with the onset of mechanosensitivity. Antibodies to TRPA1 labeled hair bundles, especially at their tips, and tip labeling disappeared when the transduction apparatus was chemically disrupted. Inhibition of TRPA1 protein expression in zebrafish and mouse inner ears inhibited receptor cell function, as assessed with electrical recording and with accumulation of a channel-permeant fluorescent dye.
Bandell et al. (2004) demonstrated that mouse and human TRPA1 channels were activated by noxious cold temperature. In addition, the mouse Trpa1 channel was activated by pungent natural compounds present in cinnamon oil (cinnamaldehyde), wintergreen oil (methyl salicylate), clove oil (eugenol), mustard oil (allyl isothiocyanate; AITC), and ginger (gingerol), all of which are known to cause a burning sensation in humans. Bradykinin, an inflammatory peptide involved in nociception, also activated Trpa1 channels via the bradykinin receptor-2 (BDKRB2; 113503), possibly via a phospholipase C (see 172420)-related mechanism. Cinnamaldehyde predominantly excited cold-sensitive dorsal root ganglion cells in culture and elicited nociceptive behavior in mice. Bandell et al. (2004) suggested that Trpa1 activation by cold temperature may convey a paradoxical burning pain sensation.
Garlic belongs to the Allium family of plants that also includes onion, leek, chive, and shallot. Allium plants produce organosulfur compounds, such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Bautista et al. (2005) found that garlic extract, purified allicin, and DADS activated an AITC-responsive subpopulation of rodent trigeminal neurons and dissociated dorsal root ganglion cells in vitro via the TRPA1 channel. Garlic extracts also induced vasodilation of rodent mesenteric arterial segments in vitro by activating capsaicin-sensitive perivascular sensory nerve endings. The findings were consistent with the theory that certain plants have developed strategies to achieve chemical deterrence. Macpherson et al. (2005) showed that allicin is the chemical responsible for TRPA1 and TRPV1 activation by raw garlic.
In experiments in male Sprague-Dawley rats, Obata et al. (2005) demonstrated that pharmacologic blockade of TRPA1 by anti-nerve growth factor (NGF; see 162030), p38 MAPK (600289) inhibitor, or TRPA1 antisense oligodeoxynucleotide in primary sensory neurons reversed cold hyperalgesia caused by inflammation and nerve injury. Obata et al. (2005) concluded that an NGF-induced TRPA1 increase in sensory neurons via p38 activation is necessary for cold hyperalgesia.
Hinman et al. (2006) noted that the diverse chemical nature of TRPA1-activating irritants suggests that their reactivity, rather than their chemical structure, is critical in TRPA1 activation. By examining Xenopus oocytes expressing wildtype and mutant human TRPA1, they found that structurally distinct environmental irritants activated TRPA1 by a reversible covalent modification of cysteine residues at positions 619, 639, and 663 (and to a lesser extent lys708) within the putative cytoplasmic N-terminal domain of the channel.
Macpherson et al. (2007) observed that most compounds known to activate TRPA1 are able to covalently bind cysteine residues. They used click chemistry to show that derivatives of 2 such compounds, mustard oil and cinnamaldehyde, covalently bind mouse Trpa1. Structurally unrelated cysteine-modifying agents such as iodoacetamide (IA) and (2-aminoethyl)methanethiosulfonate (MTSEA) also bind and activate TRPA1. Macpherson et al. (2007) identified by mass spectrometry 14 cytosolic TRPA1 cysteines labeled by IA, 3 of which are required for normal channel function. In excised patches, reactive compounds activated TRPA1 currents that were maintained at least 10 minutes after washout of the compound in calcium-free solutions. Finally, activation of TRPA1 by disulfide bond-forming MTSEA was blocked by the reducing agent dithiothreitol (DTT). Macpherson et al. (2007) collectively concluded that covalent modification of reactive cysteines within TRPA1 can cause channel activation, rapidly signaling potential tissue damage through the pain pathway.
Dai et al. (2007) provided evidence for a mechanism in which the proteases trypsin (276000) or tryptase (191080) activate PAR2 (600933), which in turn sensitizes TRPA1. Trpa1 and Par2 colocalized in primary afferent neurons within rat dorsal root ganglia, and patch-clamp studies in HEK293 cells showed that PAR2 agonists increased TRPA1 currents. The increased sensitivity of TRPA1 was due to phospholipase C (see 172420), which hydrolyzes plasma membrane phosphatidylinositol-4,5-bisphosphate (PIP2) and thus releases PIP2-mediated inhibition of TRPA1. Studies in rats showed that AITC- or cinnamaldehyde-evoked pain behavior was enhanced by Par2 activation in vivo.
4-hydroxy-2-nonenal (HNE) is an endogenous aldehyde that is produced when reactive oxygen species (ROS) peroxidate membrane phospholipids in response to tissue injury, inflammation, and oxidative stress. Trevisani et al. (2007) showed that HNE activated Trpa1 on mouse nociceptive neurons to promote acute pain, neuropeptide release, and neurogenic inflammation. McNamara et al. (2007) showed that Trpa1 is the principal site of formalin-induced pain in rodents and that formalin excites sensory neurons by directly activating Trpa1.
Snakes possess a unique sensory system for detecting infrared radiation, enabling them to generate a 'thermal image' of predators or prey. Infrared signals are initially received by the pit organ, a highly specialized facial structure that is innervated by nerve fibers of the somatosensory system. Gracheva et al. (2010) used an unbiased transcriptional profiling approach to identify TRPA1 channels as infrared receptors on sensory nerve fibers that innervate the pit organ. The authors found that TRPA1 orthologs from pit-bearing snakes (vipers, pythons, and boas) were the most heat-sensitive vertebrate ion channels identified to that time, consistent with their role as primary transducers of infrared stimuli. Thus, snakes detect infrared signals through a mechanism involving radiant heating of the pit organ, rather than photochemical transduction.
Weng et al. (2015) noted that TRPV1 interacts with TRPA1 and inhibits its activity in dorsal root ganglion (DRG) neurons. They found that Tmem100 (616334) was expressed in Trpa1- and Trpv1-positive mouse DRG neurons and that Tmem100 interacted with both Trpa1 and Trvp1 in coimmunoprecipitation and protein pull-down assays. Tmem100 weakened the association of Trpa1 with Trpv1, thereby reducing Trpv1-mediated inhibition of Trpa1 in DRG neurons. Tmem100 also increased Trpa1 activity when coexpressed with Trpa1 and Trpv1 in CHO and HEK293T cells. Tmem100 increased the open probability of Trpa1 channels in response to chemical pain signals, but only in the presence of Trpv1. Tmem100 also increased cell surface expression of Trpa1 and Trpv1. Selective elimination of Tmem100 in mouse DRG primary sensory neurons reduced the responses of these mice to noxious chemical, mechanical, and inflammatory stimuli, but had no effect on cold-induced pain responses. Patch-clamp recordings of Tmem100-knockout DRG neurons revealed reduced capsaicin-evoked Trpa1 activity compared with controls. Weng et al. (2015) concluded that TMEM100 is an adaptor protein that regulates the association between TRPA1 and TRPV1.
In ischemia myelin is damaged in a Ca(2+)-dependent manner, abolishing action potential propagation. This had been attributed to glutamate release activating Ca(2+)-permeable N-methyl-D-aspartate (NMDA) receptors. Hamilton et al. (2016) showed that NMDA does not raise the intracellular Ca(2+) concentration ([Ca(2+)]i) in mature oligodendrocytes and that, although ischemia evokes a glutamate-triggered membrane current, this is generated by a rise of extracellular [K+] and decrease of membrane K+ conductance. Nevertheless, ischemia raises oligodendrocyte [Ca(2+)]i, [Mg(2+)]i and [H+]i, and buffering intracellular pH reduces the [Ca(2+)]i and [Mg(2+)]i increases, showing that these are evoked by the rise of [H+]i. The H(+)-gated [Ca(2+)]i elevation is mediated by channels with characteristics of TRPA1, being inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079, or TRPA1 knockout. TRPA1 block reduces myelin damage in ischemia.
Su et al. (2016) assessed the impact of Trpa1 and Trpv1 on behavioral and biochemical responses to iodine in mice in the presence or absence of specific antagonists. They found that Trpa1 is the major mediator of iodine-induced pain, with Trpv1 accounting for the remainder. Iodine-induced nociceptive responses were substantially attenuated in mice lacking Trpa1. Further analysis showed that the substance P (162320) rather than the CGRP (114130) signaling pathway was involved in the adjuvant effect of iodine on cutaneous allergy. In human cells, TRPA1, but not TRPV1, was directly activated by iodine. Su et al. (2016) proposed that local inhibition of TRPA1 and TRPV1 channels may minimize the side effects of iodine antiseptics while retaining their superior antimicrobial efficacy and lack of acquired microbial resistance.
Miyake et al. (2016) found that inhibiting hydroxylation of pro394 in human TRAP1 via mutation or use of a prolyl hydroxylase inhibitor potentiated cold sensitivity of TRPA1 in the presence of hydrogen peroxide. Likewise, sensitization of TRPA1 to reactive oxygen species (ROS) or to oxaliplatin to inhibit prolyl hydroxylation also caused cold sensitivity. Miyake et al. (2016) proposed that blocking prolyl hydroxylation reveals TRPA1 sensitization to ROS, enabling TRPA1 to convert ROS signaling to cold sensitivity.
Reactive electrophiles are a class of noxious compounds humans find pungent and irritating, such as allyl isothiocyanate (in wasabi) and acrolein (in cigarette smoke). Diverse animals, from insects to humans, find reactive electrophiles aversive, but whether this reflects conservation of an ancient sensory modality has been unclear. Kang et al. (2010) identified the molecular basis of reactive electrophile detection in flies and demonstrated that Drosophila TRPA1, the Drosophila melanogaster ortholog of the human irritant sensor, acts in gustatory chemosensors to inhibit reactive electrophile ingestion. Kang et al. (2010) showed that fly and mosquito TRPA1 orthologs are molecular sensors of electrophiles, using a mechanism conserved with vertebrate TRPA1s. Phylogenetic analyses indicate that invertebrate and vertebrate TRPA1s share a common ancestor that possessed critical characteristics required for electrophile detection. These findings supported emergence of TRPA1-based electrophile detection in a common bilaterian ancestor, with widespread conservation throughout vertebrate and invertebrate evolution. Such conservation contrasts with the evolutionary divergence of canonical olfactory and gustatory receptors and may relate to electrophile toxicity. Kang et al. (2010) proposed that human pain perception relies on an ancient chemical sensor conserved across approximately 500 million years of animal evolution.
Bautista et al. (2006) obtained Trpa1 -/- mice at the expected mendelian ratios and found that they were normal in overall appearance and viability. Calcium imaging of trigeminal neurons from wildtype and Trpa1 -/- mice showed that Trpa1 was the sole target through which mustard oil and garlic activated primary afferent nociceptors to produce inflammatory pain. The authors also showed that Trpa1 was targeted by environmental irritants, such as acrolein, that account for the toxic and inflammatory actions of tear gas, vehicle exhaust, and metabolic byproducts of chemotherapeutic agents. Trpa1 -/- mice displayed normal cold sensitivity and unimpaired auditory function, suggesting that Trpa1 is not required for the initial detection of noxious cold or sound. However, Trpa1 -/- mice exhibited pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity.
Bessac et al. (2008) showed that hypochlorite and hydrogen peroxide activated Ca(2+) influx and membrane currents in an oxidant-sensitive subpopulation of cultured mouse dorsal root ganglion neurons and that these responses were absent in neurons from Trpa1 -/- mice. In tests of respiratory function, Trpa1 -/- mice displayed profound deficiency in hypochlorite- and hydrogen peroxide-induced respiratory depression, as well as decreased oxidant-induced pain behavior.
Andre et al. (2008) found that an aqueous extract of cigarette smoke, including the alpha, beta-unsaturated aldehydes crotonaldehyde and acrolein, mobilized Ca(2+) in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione, but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with cigarette smoke extract or aldehydes increased Ca(2+) influx in Trpa1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. The effect of cigarette smoke extract and aldehydes on Ca(2+) influx in dorsal root ganglion neurons was abolished in Trpa1-deficient mice. Andre et al. (2008) concluded that the data identified alpha, beta-unsaturated aldehydes as the main causative agents in cigarette smoke that mediate airway neurogenic inflammation via TRPA1 stimulation.
Trevisan et al. (2016) showed that surgical constriction of the infraorbital nerve in mice stimulated monocyte/macrophage infiltration at the site of ligature. Infiltration of monocytes/macrophages increased oxidative stress in the infraorbital nerve and induced pain-like behaviors by enhancing Trpa1 activity.
Vandewauw et al. (2018) showed that acute noxious heat sensing in mice depends on a triad of transient receptor potential ion channels: Trpm3 (608961), Trpv1 (602076), and Trpa1. Vandewauw et al. (2018) found that robust somatosensory heat responsiveness at the cellular and behavioral level is observed only if at least 1 of these TRP channels is functional. However, combined genetic or pharmacologic elimination of all 3 channels largely and selectively prevents heat responses in both isolated sensory neurons and rapidly firing C and A-delta sensory nerve fibers that innervate the skin. Strikingly, Trpv1-/-Trpm3-/-Trpa1-/- triple-knockout mice lack the acute withdrawal response to noxious heat that is necessary to avoid burn injury, while showing normal nociceptive responses to cold or mechanical stimuli and a preserved preference for moderate temperatures. Vandewauw et al. (2018) concluded their findings indicated that the initiation of the acute heat-evoked pain response in sensory nerve endings relies on 3 functionally redundant TRP channels, representing a fault-tolerant mechanism to avoid burn injury.
Eigenbrod et al. (2019) found that various species of subterranean naked mole rats were insensitive to pain from 1 or more substances, including capsaicin, acid (HCl), or allyl isothiocyanate (AITC), an algogen produced by a South African stinging ant. Animals were tested with each of the 3 stimuli and RNA was isolated from sensory tissues for sequencing. Two of the acid-insensitive species had downregulated ASIC3 (ACCN3; 611741) and TWIK1 (KCNK1; 601745) transcripts, and others showed amino acid changes in the TRPA1 channel protein. The highveld mole rat (Cryptomys hottentotus pretoriae), which was particularly insensitive to AITC, had upregulated expression of NALCN (611549). Overexpression of NALCN increases background sodium currents associated with membrane leakiness, which acts as a shunt so that injection of current cannot as easily produce membrane depolarization, and therefore dampens pain perception. Animals treated with verapamil, an NALCN blocker, responded strongly to AITC injections. Eigenbrod et al. (2019) concluded that pain insensitivity in mole rat species has been driven by a combination of selection for the ability to feed on pungent plants and, for the highveld mole rat, the ability to coexist with aggressive stinging ants.
De Logu et al. (2019) showed that alcohol dehydrogenase (ADH; see 103700) converted ethanol to acetaldehyde in mouse liver and in Schwann cells of mouse paw. Acetaldehyde generated in the Schwann cells activated Trpa1 and initiated sustained allodynia by increasing oxidative stress in response to administration of alcohol in mouse paw. Similarly, chronic ethanol ingestion promoted oxidative stress and allodynia through Schwann cell Trpa1 activation in mice. The authors recapitulated the same mechanism of ethanol-evoked ADH- and TRPA1-dependent increase of oxidative stress in human Schwann cells.
By linkage analysis followed by candidate gene sequencing in a large Colombian family with episodic pain syndrome (FEPS1; 615040), Kremeyer et al. (2010) identified a heterozygous missense mutation in the TRPA1 gene (N855S; 604775.0001). The disorder was characterized by onset at birth of episodic debilitating pain affecting the upper body in response to triggers such as hunger, fatigue, and cold. In vitro functional expression studies indicated that the mutation resulted in a gain of function of channel activity.
In affected members of a large 4-generation Colombian family with autosomal dominant familial episodic pain syndrome (FEPS1; 615040), Kremeyer et al. (2010) identified a heterozygous 2564A-G transition in exon 22 of the TRPA1 gene, resulting in an asn855-to-ser (N855S) substitution in transmembrane segment S4. The mutation segregated completely with the phenotype and was not found in 139 ethnically matched controls. HEK293 cells transfected with the mutation had a 5-fold increase in inward current when stimulated by the agonist cinnamaldehyde compared to wildtype at normal neuronal resting potential. The increased current was accompanied by a leftward shift in the midpoint of voltage activation curves, but also appeared to affect calcium-dependent channel gating. Ligand binding was not affected, and the mutant channel could be blocked by a selective antagonist. The findings were consistent with a gain of function.
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Gross, M. B. Personal Communication. Baltimore, Md. 3/3/2021.
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