Transient receptor potential cation channel, member A1
|Transient receptor potential cation channel, subfamily A, member 1|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
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 environmental irritants, pain, cold and stretch.
TRPA1 is a member of the transient receptor potential channel family. TRPA1, contains 14 N-terminal ankyrin repeats and is believed to function as a mechanical stress sensor. The specific function of this protein has not yet been determined; however, studies indicate that the function may involve a role in signal transduction and growth control.
Recent studies indicate that TRPA1 is activated by a number of reactive  (allyl isothiocyanate, cinnamaldehyde, farnesyl thiosalicylic acid, formalin, hydrogen peroxide, 4-hydroxynonenal, acrolein, and tear gases) and non-reactive compounds (nicotine, PF-4840154) and considered as a 'chemosensor' in the body. TRPA1 is considered as an attractive pain target based on the fact that TRPA1 knockout mice showed near complete attenuation of formalin-induced pain behaviors. TRPA1 antagonists are effective in blocking pain behaviors induced by inflammation (complete Freund's adjuvant and formalin).
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 causing the skin irritation experienced by some smokers trying to quit by using nicotine replacement therapies such as inhalers, sprays, or patches. 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.
Metabolites of paracetamol (acetaminophen) have been demonstrated to activate TRPA1 receptors in the spinal cord of mice, causing an antinociceptive effect. This is suggested as the antinociceptive mechanism for paracetamol.
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.
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. For a broad range of electrophilic agents, chemical reactivity in combination with a lipophilicity enabling membrane permeation is crucial to TRPA1 agonistic effect. A dibenz[b,f][1,4]oxazepine derivative substituted by a carboxylic methylester at position 10 is the most potent TRPA1 agonist discovered to date (EC50 = 50 pM). The pyrimidine PF-4840154 is a potent, non covalent inhibitor 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.
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- Kremeyer B et al. (June 2010). "A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome". Neuron 66 (5): 671–680. doi:10.1016/j.neuron.2010.04.030. PMID 20547126.
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- Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG, Cravatt BF, Patapoutian A (February 2007). "Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines". Nature 445 (7127): 541–5. doi:10.1038/nature05544. PMID 17237762.
- Gijsen HJ, Berthelot D, Zaja M, Brône B, Geuens I, Mercken M (October 2010). "Analogues of Morphanthridine and the Tear Gas Dibenz[b,f][1,4]oxazepine (CR) as Extremely Potent Activators of the Human Transient Receptor Potential Ankyrin 1 (TRPA1) Channel". J Med Chem 53 (19): 7011–7020. doi:10.1021/jm100477n. PMID 20806939.