Transient receptor potential cation channel, member A1

Transient receptor potential cation channel, subfamily A, member 1
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3J9P
Identifiers
Symbols	TRPA1 ; ANKTM1; FEPS
External IDs	OMIM: 604775 MGI: 3522699 HomoloGene: 7189 IUPHAR: 485 ChEMBL: 6007 GeneCards: TRPA1 Gene
Gene ontology Molecular function • intracellular ligand-gated calcium channel activity • channel activity • temperature-gated cation channel activity Cellular component • plasma membrane • integral component of plasma membrane • stereocilium bundle Biological process • ion transport • cell surface receptor signaling pathway • response to cold • response to organic substance • response to organic cyclic compound • sensory perception of pain • ion transmembrane transport • response to drug • response to hydrogen peroxide • response to pain • thermoception • detection of mechanical stimulus involved in sensory perception of pain • detection of chemical stimulus involved in sensory perception of pain • protein homotetramerization • transmembrane transport • calcium ion transmembrane transport Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	8989	277328
Ensembl	ENSG00000104321	ENSMUSG00000032769
UniProt	O75762	Q8BLA8
RefSeq (mRNA)	NM_007332	NM_177781
RefSeq (protein)	NP_015628	NP_808449
Location (UCSC)	Chr 8: 72.02 – 72.08 Mb	Chr 1: 14.87 – 14.92 Mb
PubMed search	[1]	[2]

Transient receptor potential cation channel, subfamily A, member 1, also known as TRPA1, is a protein that in humans is encoded by the TRPA1 (and in other species by the Trpa1) gene.

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 giving rise to somatosensory modalities such as pain, cold and itch.

Function

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 and chemical 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).

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 organs of many snakes TRPA1 is responsible for the detection of infrared radiation.

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 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.

Ligand binding

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 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.

See also

• TRPA1 receptor agonist

External links

• TRPA1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)