Transient receptor potential cation channel, member A1

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

TRPA1 is an is_associated_with::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.

Function
TRPA1 is a member of the is_associated_with::transient receptor potential channel family. TRPA1, contains 14 N-terminal is_associated_with::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 is_associated_with::signal transduction and growth control.

Recent studies indicate that TRPA1 is activated by a number of reactive (is_associated_with::allyl isothiocyanate, is_associated_with::cinnamaldehyde, farnesyl thiosalicylic acid, is_associated_with::formalin, is_associated_with::hydrogen peroxide, is_associated_with::4-hydroxynonenal, is_associated_with::acrolein, and is_associated_with::tear gases ) and non-reactive compounds (is_associated_with::nicotine, is_associated_with::PF-4840154 ) and considered as a 'is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::missense mutation of TRPA1 was found to be the cause of a hereditary episodic pain syndrome. A family from is_associated_with::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 is_associated_with::gain-of-function mutation in the fourth is_associated_with::transmembrane domain causes the channel to be overly sensitive to pharmacological activation.

Metabolites of is_associated_with::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 is_associated_with::olive oil phenolic compound is_associated_with::oleocanthal appears to be responsible for the pungent or "peppery" sensation in the back of the throat caused by is_associated_with::olive oil.

Although several nonelectrophilic agents such as is_associated_with::thymol and is_associated_with::menthol have been reported as TRPA1 agonists, most of the known activators are is_associated_with::electrophilic chemicals that have been shown to activate the TRPA1 receptor via the formation of a reversible is_associated_with::covalent bond with is_associated_with::cysteine residues present in the is_associated_with::ion channel. For a broad range of electrophilic agents, chemical reactivity in combination with a is_associated_with::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 is_associated_with::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, is_associated_with::PF-4840154 is superior to is_associated_with::allyl isothiocyanate, the pungent component of mustard oil, for screening purposes.