TRPA1

Last updated

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; OMA:TRPA1 - orthologs
Orthologs
SpeciesHumanMouse
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: 14.94 – 14.99 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, TRPA1, or The Mustard and Wasabi Receptor, is a protein that in humans is encoded by the TRPA1 (and in mice and rats by the Trpa1) gene. [5] [6]

Contents

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 pain, cold and itch in humans and other mammals, as well as a sensor for environmental irritants giving rise to other protective responses (tears, airway resistance, and cough). [7] [8]

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] One of the specific functions of this protein studies involves a role in the detection, integration and initiation of pain signals in the peripheral nervous system. [10] It can be activated at sites of tissue injury or sites of inflammation directly by endogenous mediators or indirectly as a downstream target via signaling from a number of distinct G-protein coupled receptors (GPCRs), such as bradykinin.

The role of TRPA1 in pain sensing was first revealed when TRPA1 was identified as the receptor for mustard oil (allyl isothiocyanate), the pungent ingredient in mustard and wasabi. [11] Recent studies indicate that TRPA1 is activated by a number of reactive [8] [12] (cinnamaldehyde, farnesyl thiosalicylic acid, formalin, hydrogen peroxide, 4-hydroxynonenal, acrolein, and tear gases [13] [14] [15] ) and non-reactive compounds (nicotine, [16] PF-4840154 [17] ) and is thus considered as a "chemosensor" in the body. [18] TRPA1 is co-expressed with TRPV1 on nociceptive primary afferent C-fibers in humans. [19] 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. [20] Indeed, TRPA1 is considered as an attractive pain target. TRPA1 knockout mice showed near complete attenuation of nocifensive behaviors to formalin, tear-gas and other reactive chemicals . [21] [22] TRPA1 antagonists are effective in blocking pain behaviors induced by inflammation (complete Freund's adjuvant and formalin).

Although it is not fully confirmed whether noxious cold sensation is mediated by TRPA1 in vivo, several recent studies clearly demonstrated cold activation of TRPA1 channels in vitro. [23] [24]

In the heat-sensitive loreal pit organs of many snakes, TRPA1 is responsible for the detection of infrared radiation. [25] [26]

Structure

In 2016, cryo-electron microscopy was employed to obtain a three-dimensional structure of TRPA1. This work revealed that the channel assembles as a homotetramer, and possesses several structural features that hint at its complex regulation by irritants, cytoplasmic second messengers (e.g., calcium), cellular co-factors (e.g., inorganic anions like polyphosphates), and lipids (e.g., PIP2). Most notably, the site of covalent modification and activation for electrophilic irritants was localized to a tertiary structural feature on the membrane-proximal intracellular face of the channel, which has been termed the 'allosteric nexus', and which is composed of a cysteine-rich linker domain and the eponymous TRP domain. [27] Breakthrough research combining cryo-electron microscopy and electrophysiology later elucidated the molecular mechanism of how the channel functions as a broad-spectrum irritant detector. With respect to electrophiles, which activate the channel by covalent modification of two cysteines in the allosteric nexus, it was shown that these reactive oxidative species act step-wise to modify two critical cysteine residues in the allosteric nexus. Upon covalent attachment, the allosteric nexus adopts a conformational change that is propagated to the channel's pore, dilating it to permit cation influx and subsequent cellular depolarization. With respect to activation by the second messenger calcium, the structure of the channel in complex with calcium localized the binding site for this ion and functional studies demonstrated that this site controls the various different effects of calcium on the channel – namely potentiation, desensitization, and receptor-operation. [28]

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. [29]

TRPA1 has also been implicated in airway irritation [30] by cigarette smoke, [31] cleaning supplies [15] and in the skin irritation experienced by some smokers trying to quit by using nicotine replacement therapies such as inhalers, sprays, or patches. [16] 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. [32]

Metabolites of paracetamol (acetaminophen) have been demonstrated to bind to the TRPA1 receptors, which may desensitize the receptors in the way capsaicin does in the spinal cord of mice, causing an antinociceptive effect. This is suggested as the antinociceptive mechanism for paracetamol. [33]

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). [34]

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. [35] [36]

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. [37] [38]

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. [39] [40] Another example of a nonelectrophilic agent is the anesthetic propofol, which is known to cause pain on injection into a vein, a side effect attributed to TRPV1 and TRPA1 activation. [41] A dibenz[b,f][1,4]oxazepine derivative substituted by a carboxylic methyl ester at position 10 has been reported to be a potent nonelectrophilic (thiol-unreactive) TRPA1 agonist (EC50 = 0.05 nM), while dibenzoxazepine (CR 'gas', 0.3 nM) itself, as well as several other tear gases (CN (30 nM), CS (0.9 nM), CA (10 nM) 'gases') were found to be thiol-reactive TRPA1 agonists. This study found that chemical reactivity with thiols in combination with lipophilicity enabling membrane permeation result in a potent TRPA1 agonistic effect, but thiol adduct formation is neither sufficient nor necessary for TRPA1 activation. [42] 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. [17] Other TRPA1 channel activators include JT-010 and ASP-7663, while channel blockers include A-967079, HC-030031 and AM-0902.

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 the spinal cord directly activate TRPA (and also TRPV1) receptors to augment the perception of pain. [43] [44] [45] [46] 12S-HpETE, which is the direct precursor to HxA3 and HxB3 in the ALOX12 pathway, may act only after being converted to these hepoxilins. [45] The epoxide, 5,6-epoxy-8Z,11Z,14Z-eicosatrienoic acid (5,6-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. [45]

Studies with mice, guinea pigs, and human tissues 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 [47] ), has been associated with ACE inhibitor-induce cough in humans. [48] [49]

More recently, a peptide toxin termed the wasabi receptor toxin from the Australian black rock scorpion ( Urodacus manicatus ) was discovered; it was shown to bind TRPA1 non-covalently in the same region as electrophiles and act as a gating modifier toxin for the receptor, stabilizing the channel in an open conformation. [50]

TRPA1 inhibition

A number of small molecule inhibitors (antagonists) have been discovered which have been shown to block the function of TRPA1. [51] At the cellular level, assays that measure agonist-activated inhibition of TRPA1-mediated calcium fluxes and electrophysiological assays have been used to characterize the potency, species specificity and mechanism of inhibition. While the earliest inhibitors, such as HC-030031, were lower potency (micromolar inhibition) and had limited TRPA1 specificity, the more recent discovery of highly potent inhibitors with low nanomolar inhibition constants, such as A-967079 and ALGX-2542 as well as high selectivity among other members the TRP superfamily and lack of interaction with other targets have provided valuable tool compounds and candidates for future drug development. [51] [52] [53]

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. [54] [55] [56] [57] [58]

Ligand examples

Agonists

Gating Modifiers

Antagonists

Related Research Articles

Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC, TRPV, TRPVL, TRPM, TRPS, TRPN, and TRPA. Group 2 consists of TRPP and TRPML. Other less-well categorized TRP channels exist, including yeast channels and a number of Group 1 and Group 2 channels present in non-animals. Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of taste, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic (allicin), chili pepper (capsaicin), wasabi ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration. Most of the channels are activated or inhibited by signaling lipids and contribute to a family of lipid-gated ion channels.

<span class="mw-page-title-main">Hepoxilin</span> Chemical compound

Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid derived from acid the (PUFA), arachidonic acid. A second group of less well studied hepoxilins, HxA4, HxB4, and their non-enzymatically formed isomers are nonclassical eicosanoids derived from the PUFA, eicosapentaenoic acid. Recently, 14,15-HxA3 and 14,15-HxB3 have been defined as arachidonic acid derivatives that are produced by a different metabolic pathway than HxA3, HxB3, HxA4, or HxB4 and differ from the aforementioned hepoxilins in the positions of their hydroxyl and epoxide residues. Finally, hepoxilin-like products of two other PUFAs, docosahexaenoic acid and linoleic acid, have been described. All of these epoxyalcohol metabolites are at least somewhat unstable and are readily enzymatically or non-enzymatically to their corresponding trihydroxy counterparts, the trioxilins (TrX). HxA3 and HxB3, in particular, are being rapidly metabolized to TrXA3, TrXB3, and TrXC3. Hepoxilins have various biological activities in animal models and/or cultured mammalian tissues and cells. The TrX metabolites of HxA3 and HxB3 have less or no activity in most of the systems studied but in some systems retain the activity of their precursor hepoxilins. Based on these studies, it has been proposed that the hepoxilins and trioxilins function in human physiology and pathology by, for example, promoting inflammation responses and dilating arteries to regulate regional blood flow and blood pressure.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. Fatty acid metabolites with affinity for this receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA). The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). In primary afferent sensory neurons, it cooperates with TRPA1 to mediate the detection of noxious environmental stimuli.

<span class="mw-page-title-main">TRPV</span> Subgroup of TRP cation channels named after the vanilloid receptor

TRPV is a family of transient receptor potential cation channels in animals. All TRPVs are highly calcium selective.

<span class="mw-page-title-main">TRPA (ion channel)</span> Family of transport proteins

TRPA is a family of transient receptor potential ion channels. The TRPA family is made up of 7 subfamilies: TRPA1, TRPA- or TRPA1-like, TRPA5, painless, pyrexia, waterwitch, and HsTRPA. TRPA1 is the only subfamily widely expressed across animals, while the other subfamilies are largely absent in deuterostomes.

<span class="mw-page-title-main">TRPM5</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M member 5 (TRPM5), also known as long transient receptor potential channel 5 is a protein that in humans is encoded by the TRPM5 gene.

<span class="mw-page-title-main">TRPV2</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene. TRPV2 is a nonspecific cation channel that is a part of the TRP channel family. This channel allows the cell to communicate with its extracellular environment through the transfer of ions, and responds to noxious temperatures greater than 52 °C. It has a structure similar to that of potassium channels, and has similar functions throughout multiple species; recent research has also shown multiple interactions in the human body.

<span class="mw-page-title-main">TRPV4</span> Protein-coding gene in humans

Transient receptor potential cation channel subfamily V member 4 is an ion channel protein that in humans is encoded by the TRPV4 gene.

<span class="mw-page-title-main">TRPM8</span> Protein-coding gene in humans

Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.

<span class="mw-page-title-main">TRPM3</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M member 3 is a protein that in humans is encoded by the TRPM3 gene.

<span class="mw-page-title-main">TRPV3</span> Protein-coding gene in humans

Transient receptor potential cation channel, subfamily V, member 3, also known as TRPV3, is a human gene encoding the protein of the same name.

Relief from chronic pain remains a recognized unmet medical need. Consequently, the search for new analgesic agents is being intensively studied by the pharmaceutical industry. The TRPV1 receptor is a ligand gated ion channel that has been implicated in mediation of many types of pain and therefore studied most extensively. The first competitive antagonist, capsazepine, was first described in 1990; since then, several TRPV1 antagonists have entered clinical trials as analgesic agents. Should these new chemical entities relieve symptoms of chronic pain, then this class of compounds may offer one of the first novel mechanisms for the treatment of pain in many years.

<span class="mw-page-title-main">David Julius</span> American physiologist and Nobel laureate 2021

David Jay Julius is an American physiologist and Nobel Prize laureate known for his work on molecular mechanisms of pain sensation and heat, including the characterization of the TRPV1 and TRPM8 receptors that detect capsaicin, menthol, and temperature. He is a professor at the University of California, San Francisco.

<span class="mw-page-title-main">9-Hydroxyoctadecadienoic acid</span> Chemical compound

9-Hydroxyoctadecadienoic acid (or 9-HODE) has been used in the literature to designate either or both of two stereoisomer metabolites of the essential fatty acid, linoleic acid: 9(S)-hydroxy-10(E),12(Z)-octadecadienoic acid (9(S)-HODE) and 9(R)-hydroxy-10(E),12(Z)-octadecadienoic acid (9(R)-HODE); these two metabolites differ in having their hydroxy residues in the S or R configurations, respectively. The accompanying figure gives the structure for 9(S)-HETE. Two other 9-hydroxy linoleic acid derivatives occur in nature, the 10E,12E isomers of 9(S)-HODE and 9(R)-HODE viz., 9(S)-hydroxy-10E,12E-octadecadienoic acid (9(S)-EE-HODE) and 9(R)-hydroxy-10E,12E-octadecadienoic acid (13(R)-EE-HODE); these two derivatives have their double bond at carbon 12 in the E or trans configuration as opposed to the Z or cis configuration. The four 9-HODE isomers, particularly under conditions of oxidative stress, may form together in cells and tissues; they have overlapping but not identical biological activities and significances. Because many studies have not distinguished between the S and R stereoisomers and, particularly in identifying tissue levels, the two EE isomers, 9-HODE is used here when the isomer studied is unclear.

The transient receptor potential Ca2+ channel (TRP-CC) family (TC# 1.A.4) is a member of the voltage-gated ion channel (VIC) superfamily and consists of cation channels conserved from worms to humans. The TRP-CC family also consists of seven subfamilies (TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML) based on their amino acid sequence homology:

  1. the canonical or classic TRPs,
  2. the vanilloid receptor TRPs,
  3. the melastatin or long TRPs,
  4. ankyrin (whose only member is the transmembrane protein 1 [TRPA1])
  5. TRPN after the nonmechanoreceptor potential C (nonpC), and the more distant cousins,
  6. the polycystins
  7. and mucolipins.

Specialized pro-resolving mediators are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of lipoxygenase, cyclooxygenase, and cytochrome P450 monooxygenase enzymes. Pre-clinical studies, primarily in animal models and human tissues, implicate SPM in orchestrating the resolution of inflammation. Prominent members include the resolvins and protectins.

<span class="mw-page-title-main">Wasabi receptor toxin</span>

Wasabi receptor toxin (WaTx) is the active component of the venom of the Australian black rock scorpion Urodacus manicatus. WaTx targets TRPA1, also known as the wasabi receptor or irritant receptor. WaTx is a cell-penetrating toxin that stabilizes the TRPA1 channel open state while reducing its Ca2+-permeability, thereby eliciting pain and pain hypersensitivity without the neurogenic inflammation that typically occurs in other animal toxins.

<span class="mw-page-title-main">A-967079</span> Chemical compound

A-967079 is a drug which acts as a potent and selective antagonist for the TRPA1 receptor. It has analgesic and antiinflammatory effects and is used in scientific research, but has not been developed for medical use.

<span class="mw-page-title-main">JT-010</span> Chemical compound

JT-010 is a chemical compound which acts as a potent, selective activator of the TRPA1 channel, and has been used to study the role of this receptor in the perception of pain, as well as other actions such as promoting repair of dental tissue after damage.

<span class="mw-page-title-main">AMG-517</span> Chemical compound

AMG-517 is a drug which acts as a potent and selective blocker of the TRPV1 ion channel. It was developed as a potential treatment for chronic pain, but while it was an effective analgesic in animal studies it was dropped from human clinical trials at Phase I due to producing hyperthermia as a side effect, as well as poor water solubility. It is still used in scientific research into the function of the TRPV1 channel and its role in pain and inflammation, and has been used as a template for the design of several newer analogues which have improved properties.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032769 – Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  19. ↑ Nielsen TA, Eriksen MA, Gazerani P, Andersen HH (October 2018). "Psychophysical and vasomotor evidence for interdependency of TRPA1 and TRPV1-evoked nociceptive responses in human skin: an experimental study". Pain. 159 (10): 1989–2001. doi:10.1097/j.pain.0000000000001298. PMID   29847470. S2CID   44150443.
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