TRPA1

TRP channels are phylogenetic early signaling pathways (they can already be detected in yeast cells). The first TRP channel was identified in 1989 in connection with visual perception in Drosophila melanogaster. In a mutant of Drosophila (trp343), it was shown that its photoreceptors responded to light stimuli only with a transient, i.e. rapidly inactivating membrane current. In the non-mutated wild type, however, the current flow persisted as long as light hit the photoreceptor. The mutant protein -TRP- was cloned in 1989. Thus, the name "transient receptor potential" - TRP- refers to the description of a phenotype of a mutant of the fruit fly Drosophila melanogaster.

TRP channels exert important functions in primary signaling pathways for the regulated influx of Ca2+ into a cell in both vertebrates and non-vertebrates. To date, 28 TRP channel genes have been identified in mammals (Nilius B et al. 2011). In humans, TRP channels play an important role in the sensation of different types of taste (sweet, bitter, umami) as well as in the perception of pain, heat, hot or cold, pressure and light. It is assumed that some TRP channels in the body behave like microscopic thermosensors.

Some TRP channels are activated by molecules contained in spices such as garlic(allicin), chili pepper(capsaicin), wasabi (allyl isothiocyanate). Others are activated by menthol, camphor, peppermint and cooling agents. Still others are activated by molecules found in cannabis (i.e. THC, CBD and CBN). Some act as sensors of osmotic pressure, volume, stretch and vibration.

TRP channelopathies are caused by mutations in genes that encode TRP channels. Several hereditary diseases in humans (so-called "TRP channelopathies") that affect the cardiovascular, renal, skeletal, nervous system and endocrine organs are summarized under this name (Nilius B et al. 2011). TRP channels are also promising targets for drug development. For example, a number of potent small molecule TRPV1 channel antagonists (occasionally also TRPM8 antagonists) are now showing therapeutic benefit in the treatment of inflammatory and neuropathic pain (Moran MM et al. 2018).

TRPA1 (acronym for "transient receptor potential cation channel, subfamily A, member 1"), is a protein that in humans is encoded by the TRPA1 gene located on chromosome 8q21.11 (Kremeyer B et al. 2010). TRPA1 is an ion channel located on the plasma membrane of many human (and animal) cells. In humans, this ion channel serves as a chemosensor that also responds to thermal and mechanical stimuli (Logashina YA et al. 2019, Andersen HH et al. 2015). TRPA1 triggers after its activation versch. Protective responses such as lacrimation, increased airway resistance and coughing). The noxious sensation of cold is also likely transduced through TRPA1 channels. Furthermore, TRPA1 appears to be an essential component of the mechanosensitive transduction channel of vertebrate hair cells (Corey et al. 2004).

Structurally, TRPA1 contains 14 N-terminal ankyrin repeats (ankyrin-repeats). "Ankyrins" are a family of proteins, called repeat proteins, that contain ankyrin-like repeats in their structure. Ankyrins occupy key roles in activities such as cell motility, activation, proliferation, contact, and maintenance of specialized membrane domains. Using cryo-electron microscopy, a three-dimensional structure of TRPA1 could be visualized. It is shown that the ion channel is assembled as a homotetramer and has several structural features that indicate its complex functions.

TRPA1 is expressed together with TRPV1 on nociceptive primary afferent C-fibers in humans. This subpopulation of peripheral C-fibers is considered an important nociception sensor in humans, and its activation leads to pain under normal conditions. Thus, it seems indisputable that one of the functions of TRPA1 is the detection, integration, and initiation of pain signals in the peripheral nervous system. For example, in lesional areas (traumatic or inflammatory), neuronal signals are initiated directly by endogenous mediators (e.g., bradykinin) or indirectly via various G-protein-coupled receptors.

Furthermore, TRPA1 is considered a "chemosensor" in the body. Thus, TRPA1 is activated by a number of reactive substances such as: allyl isothiocyanate (pungent components of mustard, horseradish and wasabi), cinnamaldehyde, farnesylthiosalicylic acid, formalin, hydrogen peroxide, 4-hydroxynonenal and acrolein and non-reactive compounds such as nicotine among others (McNamara CR et al. 2007). Versch. animal experimental results suggest that caffeine suppresses human TRPA1 activity.

Metabolites of acetaminophen (paracetaminophen) have been shown to bind to TRPA1 receptors, which may result in receptor desensitization. This is proposed as an antinociceptive mechanism for paracetamol.

A missense mutation of TRPA1 was found to be the cause of autosomal dominant inherited episodic pain syndrome (OMIM: 615040; reviewed in Kremeyer B et al. 2010).

Oxalate, a metabolite of oxaliplatin, has been shown to inhibit prolyl hydroxylase, which confers a kind of "pseudocold sensitivity" to cold-insensitive human TRPA1 (via reactive oxygen production from mitochondria). This may cause a characteristic side effect of oxaliplatin (cold-induced acute peripheral neuropathy (Miyake T et al. (2016)

TRPA1 can be considered as one of the most "promiscuous" TRP ion channels. It is apparently activated by a large number of mostly electrophilic chemicals. They form reversible covalent bonds with cysteine residues present in the ion channel. These include the agonistic ligands: allicin, allyl isothiocyanates, cannabidiol, gingerol, icilin, polygodial, hepoxilins A3 and B3, cinnamaldehydes [Lim JY et al (2015). Activation of the TRPA1 ion channel by the phenolic olive oil compound oleocanthal appears to be responsible for the olive oil-induced pungent or "peppery" sensation in the posterior pharynx.

Bradykinin activates TRPA1 via its G-protein-coupled receptor. At the same time, the involvement of phospholipase C was verified as an important component in the signal transduction pathway of TRPA1 activation. For some non-electrophilic agents such as thymol and menthol, the activation mechanism of TRPA1 is unclear.

Pharmacologically-therapeutically, TRPA1 is considered an attractive pain target. For example, TRPA1 knockout mice show near complete attenuation of nociceptive behavior to formalin and other reactive chemicals. TRPA1 antagonists are effective in blocking pain behaviors induced by inflammation (complete Freund's adjuvant and formalin).

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