TRPA1
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Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Wasabi Receptor, is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''TRPA1'' (and in mice and rats by the ''Trpa1'')
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. TRPA1 is an
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
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).


Function

TRPA1 is a member of the
transient receptor potential channel Transient receptor potential channels (TRP 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 ( "C" for canonical), TR ...
family. TRPA1 contains 14 N-terminal
ankyrin repeat The ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and ''Drosophila'' Notch. Domains consisting of ankyrin tandem repeats mediate prote ...
s and is believed to function as a mechanical and chemical stress sensor. 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. 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. Recent studies indicate that TRPA1 is activated by a number of reactive (
allyl isothiocyanate Allyl isothiocyanate (AITC) is an organosulfur compound (formula CH2CHCH2NCS). This colorless oil is responsible for the pungent taste of mustard, radish, horseradish, and wasabi. This pungency and the lachrymatory effect of AITC are mediated thr ...
,
cinnamaldehyde Cinnamaldehyde is an organic compound with the formula(C9H8O) C6H5CH=CHCHO. Occurring naturally as predominantly the ''trans'' (''E'') isomer, it gives cinnamon its flavor and odor. It is a phenylpropanoid that is naturally synthesized by the shik ...
, farnesyl thiosalicylic acid,
formalin Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section Fo ...
,
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
,
4-hydroxynonenal 4-Hydroxynonenal, or 4-hydroxy-2-nonenal or 4-HNE or HNE, (), is an α,β-unsaturated hydroxyalkenal that is produced by lipid peroxidation in cells. 4-HNE is the primary α,β-unsaturated hydroxyalkenal formed in this process. It is a colorless ...
,
acrolein Acrolein (systematic name: propenal) is the simplest unsaturated aldehyde. It is a colorless liquid with a piercing, acrid smell. The smell of burnt fat (as when cooking oil is heated to its smoke point) is caused by glycerol in the burning fa ...
, and
tear gas Tear gas, also known as a lachrymator agent or lachrymator (), sometimes colloquially known as "mace" after the early commercial aerosol, is a chemical weapon that stimulates the nerves of the lacrimal gland in the eye to produce tears. In ad ...
es) and non-reactive compounds (
nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
,
PF-4840154 PF-4840154 is a pyrimidine derivative discovered by Pfizer at its Sandwich, Kent research center. The compound is a potent, selective activator of both the human (EC50 = 23 nM) and rat (EC50 = 97 nM) TRPA1 channels. This compound elicits nocicept ...
) and is thus considered as a " chemosensor" in the body. TRPA1 is co-expressed with
TRPV1 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 th ...
on nociceptive primary afferent C-fibers in humans. This sub-population of peripheral C-fibers is considered important sensors of
nociception Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the sensory nervous system's process of encoding noxious stimuli. It deals with a series of events and processes required for an organism to receive a painful stimulus, co ...
in
humans Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
and their activation will under normal conditions give rise to
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
. Indeed, TRPA1 is considered as an attractive pain
target Target may refer to: Physical items * Shooting target, used in marksmanship training and various shooting sports ** Bullseye (target), the goal one for which one aims in many of these sports ** Aiming point, in field artillery, fi ...
. TRPA1 knockout mice showed near complete attenuation of nocifensive behaviors to formalin, tear-gas and other reactive chemicals . TRPA1 antagonists are effective in blocking pain behaviors induced by inflammation (complete
Freund's adjuvant Freund's adjuvant is a solution of antigen emulsified in mineral oil and used as an immunopotentiator (booster). The complete form, Freund's Complete Adjuvant (FCA or CFA) is composed of inactivated and dried mycobacteria (usually '' M. tuberculos ...
and formalin). Although it is not firmly confirmed whether noxious cold sensation is mediated by TRPA1 in vivo, several recent studies clearly demonstrated cold activation of TRPA1 channels in vitro. In the heat-sensitive
loreal pit The loreal pit is the deep depression, or fossa, in the loreal area on either side of the head in pit vipers (crotaline snakes). The area is located behind the nostril and in front of the eye, but below the line that runs between the centers o ...
organs of many snakes TRPA1 is responsible for the detection of infrared radiation. Snakes have this type of receptors in their pit organ to help them detect infrared radiation. However, frogs such as ''
Hyalinobatrachium fleischmanni ''Hyalinobatrachium fleischmanni'', also known as Fleischmann's glass frog or the northern glass frog, is a species of frog in the family Centrolenidae. It is found in the tropical Americas from southern Mexico to Ecuador. Specifically, these fro ...
'' can reflect infrared light with their skins and if the environment also reflect infrared light, the frogs won't be discovered by the predators.


Structure

In 2016,
cryo-electron microscopy Cryogenic electron microscopy (cryo-EM) is a cryomicroscopy technique applied on samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An aqueous sample sol ...
was employed to obtain a three-dimensional structure of TRPA1. This work revealed that the channel assembles as a
homotetramer A tetrameric protein is a protein with a protein quaternary structure, quaternary structure of four subunits (tetrameric). Homotetramers have four identical Protein subunit, subunits (such as glutathione S-transferase), and heterotetramers are M ...
, and possesses several structural features that hint at its complex regulation by irritants, cytoplasmic
second messengers Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
(e.g., calcium), cellular co-factors (e.g., inorganic anions like polyphosphates), and lipids (e.g.,
PIP2 Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
). 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. Breakthrough research combining cryo-electron microscopy and
electrophysiology Electrophysiology (from Greek , ''ēlektron'', "amber" etymology of "electron"">Electron#Etymology">etymology of "electron" , ''physis'', "nature, origin"; and , '' -logia'') is the branch of physiology that studies the electrical properties of b ...
later elucidated the molecular mechanism of how the channel functions as a broad-spectrum irritant detector. With respect to
electrophiles In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries ...
, 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.


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. TRPA1 has also been implicated in airway irritation by cigarette smoke, cleaning supplies and in the skin irritation experienced by some smokers trying to quit by using nicotine replacement therapies such as inhalers, sprays, or patches. A
missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...
of TRPA1 was found to be the cause of a hereditary episodic pain syndrome. A family from
Colombia Colombia (, ; ), officially the Republic of Colombia, is a country in South America with insular regions in North America—near Nicaragua's Caribbean coast—as well as in the Pacific Ocean. The Colombian mainland is bordered by the Car ...
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 biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
in the fourth
transmembrane domain A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bil ...
causes the channel to be overly sensitive to pharmacological activation. Metabolites of
paracetamol Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
(acetaminophen) have been demonstrated to bind to the TRPA1 receptors, which may desensitize the receptors in the way
capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burning ...
does in the spinal cord of mice, causing an antinociceptive effect. This is suggested as the antinociceptive mechanism for paracetamol. 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).


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. Activation of the TRPA1 ion channel by the
olive oil Olive oil is a liquid fat obtained from olives (the fruit of ''Olea europaea''; family Oleaceae), a traditional tree crop of the Mediterranean Basin, produced by pressing whole olives and extracting the oil. It is commonly used in cooking: f ...
phenolic Phenolic is an adjective and a substantive (noun) that may apply to : * Phenol (or carbolic acid), a colorless crystalline solid and aromatic compound * Phenols, a class of chemical compounds that include phenol * Phenolic content in wine * Phenol ...
compound
oleocanthal Oleocanthal is a phenylethanoid, or a type of natural phenolic compound found in extra-virgin olive oil. It appears to be responsible for the burning sensation that occurs in the back of the throat when consuming such oil. Oleocanthal is a tyroso ...
appears to be responsible for the pungent or "peppery" sensation in the back of the throat caused by
olive oil Olive oil is a liquid fat obtained from olives (the fruit of ''Olea europaea''; family Oleaceae), a traditional tree crop of the Mediterranean Basin, produced by pressing whole olives and extracting the oil. It is commonly used in cooking: f ...
. Although several nonelectrophilic agents such as
thymol Thymol (also known as 2-isopropyl-5-methylphenol, IPMP), , is a natural monoterpenoid phenol derivative of ''p''-Cymene, isomeric with carvacrol, found in oil of thyme, and extracted from ''Thymus vulgaris'' (common thyme), ajwain, and vario ...
and
menthol Menthol is an organic compound, more specifically a monoterpenoid, made synthetically or obtained from the oils of corn mint, peppermint, or other mints. It is a waxy, clear or white crystalline substance, which is solid at room temperature and ...
have been reported as TRPA1 agonists, most of the known activators are
electrophilic In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carri ...
chemicals that have been shown to activate the TRPA1 receptor via the formation of a reversible
covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
bond with
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
residues present in the
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
. Another example of a nonelectrophilic agent is the anesthetic
propofol Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation f ...
, which is known to cause pain on injection into a vein, a side effect attributed to
TRPV1 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 th ...
and TRPA1 activation. For a broad range of electrophilic agents, chemical reactivity in combination with a
lipophilicity Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...
enabling membrane permeation is crucial to TRPA1 agonistic effect. A dibenz 'b,f''1,4xazepine derivative substituted by a carboxylic methylester at position 10 has been reported to be a potent TRPA1 agonist (EC50 = 0.13μM or pEC50 = 6.90). The pyrimidine
PF-4840154 PF-4840154 is a pyrimidine derivative discovered by Pfizer at its Sandwich, Kent research center. The compound is a potent, selective activator of both the human (EC50 = 23 nM) and rat (EC50 = 97 nM) TRPA1 channels. This compound elicits nocicept ...
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 PF-4840154 is a pyrimidine derivative discovered by Pfizer at its Sandwich, Kent research center. The compound is a potent, selective activator of both the human (EC50 = 23 nM) and rat (EC50 = 97 nM) TRPA1 channels. This compound elicits nocicept ...
is superior to
allyl isothiocyanate Allyl isothiocyanate (AITC) is an organosulfur compound (formula CH2CHCH2NCS). This colorless oil is responsible for the pungent taste of mustard, radish, horseradish, and wasabi. This pungency and the lachrymatory effect of AITC are mediated thr ...
, the pungent component of mustard oil, for screening purposes. Other TRPA1 channel activators include
JT-010 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 Pain is a distressing feeling often caused by intense or damaging ...
and
ASP-7663 ASP-7663 is a chemical compound which acts as a potent, selective activator of the TRPA1 channel. It has protective effects on cardiac tissue, and is used for research into the function of the TRPA1 receptor. See also * JT-010 JT-010 is a chem ...
, while channel blockers include A-967079, HC-030031 and
AM-0902 AM-0902 is a drug which acts as a potent and selective Antagonist (pharmacology), antagonist for the TRPA1 receptor, and has analgesic and antiinflammatory effects. References

{{pharm-stub Purines Oxadiazoles Chloroarenes Phenyl comp ...
. The
eicosanoids Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-c ...
formed in the ALOX12 (i.e. arachidonate-12-lipoxygnease) pathway of
arachidonic acid metabolism Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
, 12''S''-hydroperoxy-5''Z'',8''Z'',10''E'',14''Z''-eicosatetraenoic acid (i.e. 12''S''-HpETE; see 12-Hydroxyeicosatetraenoic acid) and the hepoxilins (Hx), HxA3 (i.e. 8''R/S''-hydroxy-11,12-oxido-5''Z'',9''E'',14''Z''-eicosatrienoic acid) and HxB3 (i.e. 10''R/S''-hydroxy-11,12-oxido-5''Z'',8''Z'',14''Z''-eicosatrienoic acid) (see Hepoxilin#Pain perception) directly activate TRPA1 and thereby contribute to the
hyperalgesia Hyperalgesia ( or ; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can ...
and tactile
allodynia Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It i ...
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 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 th ...
) receptors to augment the perception of pain. 12''S''-HpETE, which is the direct precursor to HxA3 and HxB3 in the ALOX12 pathway, may act only after being converted to these hepoxilins. The
epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
, 5,6-epoxy-8''Z'',11''Z'',14''Z''-eicosatrienoic acid (5,6-EET) made by the metabolism of arachidonic acid by any one of several
cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzymes (see
Epoxyeicosatrienoic acid The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of Cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicosa ...
) likewise directly activates TRPA1 to amplify pain perception. Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that another arachidonic acid metabolite,
Prostaglandin E2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and ...
, operates through its prostaglandin EP3
G protein coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
to trigger
cough A cough is a sudden expulsion of air through the large breathing passages that can help clear them of fluids, irritants, foreign particles and microbes. As a protective reflex, coughing can be repetitive with the cough reflex following three pha ...
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 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 th ...
receptors. Genetic polymorphism in the EP3 receptor (rs11209716), has been associated with
ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...
-induce cough in humans. More recently, a peptide toxin termed the
wasabi receptor toxin 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 stabi ...
from the Australian black rock scorpion (''
Urodacus manicatus ''Urodacus manicatus'', commonly known as the black rock scorpion, is a species of scorpion belonging to the family Urodacidae. It is native to eastern Australia. History The black rock scorpion was described by Swedish naturalist Tamerlan Thor ...
'') 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.


TRPA1 inhibition

A number of small molecule inhibitors (antagonists) have been discovered which have been shown to block the function of TRPA1. 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. Resolvin D1 (RvD1) and RvD2 (see
resolvins Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as docosapentaenoic acid (DPA) and clupanodonic acid. As autacoids similar t ...
) and
maresin Maresin 1 (MaR1 or 7''R'',14''S''-dihydroxy-4''Z'',8''E'',10''E'',12''Z'',16''Z'',19''Z''-docosahexaenoic acid) is a macrophage-derived mediator of inflammation resolution coined from macrophage mediator in resolving inflammation. Maresin 1, an ...
1 are metabolites of the
omega 3 fatty acid Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chem ...
,
docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lino ...
. They are members of the
specialized proresolving mediators Specialized pro-resolving mediators (SPM, also termed specialized proresolving 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 ...
(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 Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
or
astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
s.
CMKLR1 Chemokine like receptor 1 also known as ChemR23 (Chemerin Receptor 23) is a protein that in humans is encoded by the ''CMKLR1'' gene. Chemokine receptor-like 1 is a G protein-coupled receptor for the chemoattractant adipokine chemerin and the ome ...
,
GPR32 G protein-coupled receptor 32, also known as GPR32 or the RvD1 receptor, is a human receptor (biochemistry) belonging to the rhodopsin-like subfamily of G protein-coupled receptors. Gene The ''GPR32'' was initially identified and defined by mo ...
,
FPR2 N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the ''FPR2'' gene and is activated to regulate cell function b ...
, and
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
s have been proposed to be the receptors through which SPMs may operate to
down-regulate In the biology, biological context of organisms' regulation of gene expression, production of gene products, downregulation is the process by which a cell (biology), cell decreases the quantity of a cellular component, such as RNA or protein, in r ...
TRPs and thereby pain perception.


Ligand examples


Agonists

* 4-Oxo-2-nonenal *
Allicin Allicin is an organosulfur compound obtained from garlic, a species in the family Alliaceae. It was first isolated and studied in the laboratory by Chester J. Cavallito and John Hays Bailey in 1944. When fresh garlic is chopped or crushed, the ...
*
Allyl isothiocyanate Allyl isothiocyanate (AITC) is an organosulfur compound (formula CH2CHCH2NCS). This colorless oil is responsible for the pungent taste of mustard, radish, horseradish, and wasabi. This pungency and the lachrymatory effect of AITC are mediated thr ...
*
ASP-7663 ASP-7663 is a chemical compound which acts as a potent, selective activator of the TRPA1 channel. It has protective effects on cardiac tissue, and is used for research into the function of the TRPA1 receptor. See also * JT-010 JT-010 is a chem ...
*
Cannabidiol Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of 113 identified cannabinoids in cannabis plants, along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. , clinical research on CBD incl ...
*
Cannabichromene Cannabichromene (CBC), also called cannabichrome, cannanbichromene, pentylcannabichromene or cannabinochromene, is an anti-inflammatory which may contribute to the pain-killing effect of cannabis. It is one of the hundreds of cannabinoids found i ...
*
Gingerol Gingerol ( gingerol) is a phenolic phytochemical compound found in fresh ginger that activates spice receptors on the tongue. It is normally found as a pungent yellow oil in the ginger rhizome, but can also form a low-melting crystalline solid. T ...
*
Icilin Icilin (AG-3-5) is a synthetic super-agonist of the transient receptor potential M8 (TRPM8) ion channel. Although structurally not related with menthol, it produces an extreme sensation of cold, both in humans and animals. It is almost 200 times ...
*
Polygodial Polygodial is chemical compound found in dorrigo pepper, mountain pepper, horopito, canelo, paracress, water-pepper, and '' Dendrodoris limbata''.M Jonassohn (1996)Sesquiterpenoid unsaturated dialdehydes - Structural properties that affect r ...
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Propofol Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation f ...
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Hepoxilin Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA), i.e. they possess both an epoxide and an alcohol (i.e. hydroxyl) residue. HxA3, HxB3, and their non-enzymatically formed isomers are nonclassic eicosanoid ...
s A3 and B3 * 12''S''-Hydroperoxy-5''Z'',8''Z'',10''E'',14''Z''-eicosatetraenoic acid * 4,5-Epoxyeicosatrienoic acid *
Cinnamaldehyde Cinnamaldehyde is an organic compound with the formula(C9H8O) C6H5CH=CHCHO. Occurring naturally as predominantly the ''trans'' (''E'') isomer, it gives cinnamon its flavor and odor. It is a phenylpropanoid that is naturally synthesized by the shik ...
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PF-4840154 PF-4840154 is a pyrimidine derivative discovered by Pfizer at its Sandwich, Kent research center. The compound is a potent, selective activator of both the human (EC50 = 23 nM) and rat (EC50 = 97 nM) TRPA1 channels. This compound elicits nocicept ...
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2-Arachidonoylglycerol 2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present ...
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Anandamide Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid rec ...
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N-Arachidonoyl dopamine ''N''-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 recep ...
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Palmitoylethanolamide Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator PEA has been studied in ''in vitro'' and ''in vivo'' systems using exogenously added or dosed compound; there is evidence that it binds to a nuclear receptor, thr ...
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Cannabidiolic acid Cannabidiolic acid (CBDA), is a cannabinoid found in cannabis plants. It is most abundant in the glandular trichomes on the female seedless flowers or more accurately infructescence often colloquially referred to as buds. CBDA is the chemical precu ...
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Cannabidivarin Cannabidivarin (CBDV, GWP42006) is a non-psychoactive cannabinoid found in ''Cannabis''. It is a homolog (chemistry) of cannabidiol (CBD), with the side-chain shortened by two methylene bridges (CH2 units). Although cannabidivarin (CBDV) is usu ...
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Cannabigerol Cannabigerol (CBG) is one of more than 120 identified cannabinoid compounds found in the plant genus ''Cannabis''. Cannabigerol is the decarboxylated form of cannabigerolic acid, the parent molecule from which other cannabinoids are synthesized. ...
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Cannabigerolic acid Cannabigerolic acid (CBGA) is the acidic form of cannabigerol (CBG). It is a dihydroxybenzoic acid and olivetolic acid in which the hydrogen at position 3 is substituted by a geranyl group. It is a biosynthetic precursor to Delta-9-tetrahydroc ...
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Cannabigerovarin Cannabigerovarin (CBGV), the propyl homolog of cannabigerol (CBG), is a cannabinoid present in ''Cannabis''. There is no observation related to the Psychoactive drug, psychoactive or psychotropic effects of CBGV when consumed or inhaled. The pos ...
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Tetrahydrocannabivarin Tetrahydrocannabivarin (THCV, THV, O-4394, GWP42004) is a Homology (chemistry), homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of a pentyl (5-carbon) group on the molecule, which makes it produce very differ ...
* Tetrahydrocannabivarin acid


Gating Modifiers

* WaTx


Antagonists

* HC-030031 * GRC17536 * A-967079 * ALGX-2513 * ALGX-2541 * ALGX-2563 * ALGX-2561 * ALGX-2542


References


External links

* {{Transient receptor potential channel modulators Membrane proteins Ion channels