TRPA1

Fig1. Molecular architecture of the human TRPA1 (hTRPA1) channel protein. (Francesco Moccia, 2023)

What is TRPA1 protein?

TRPA1 (transient receptor potential cation channel subfamily A member 1) gene is a protein coding gene which situated on the long arm of chromosome 8 at locus 8q21. TRPA1 is a non-selective cation channel that is mainly expressed in sensory neurons and plays an important role in pain perception and inflammatory response. It structurally belongs to a family of transient receptor potential (TRP) channels, members of which are named for their ability to respond to instantaneous changes in cell membrane potential. TRPA1 channels are sensitive to a variety of physical and chemical stimuli, including mechanical pressure, temperature changes, and a variety of chemical stimuli, such as mustard oil and formaldehyde. The TRPA1 protein is consisted of 1119 amino acids and its molecular mass is approximately 127.5 kDa.

What is the function of TRPA1 protein?

The TRPA1 channel acts as a low-threshold sensor that is sensitive to a variety of structurally diverse electrophilic stimuli, including small volatile poisons in the environment and endogenous pain lipids. TRPA1 can be sensitive to low temperature, mechanical and chemical stimulation, resulting in the inflow of calcium and sodium ions, membrane depolarization, and the generation of neuron action potential. The TRPA1 channel contains an EF-hand helical domain that binds to Ca2+, one of the endogenous regulators of TRPA1, which rapidly activates the channel after causing an increase in intracellular and extracellular Ca2+ concentration and enhances the response to other agonists.

Fig2. TRPA1 is a sensor of danger signals in neuronal and non-neuronal tissues. (Francesco Moccia, 2023)

TRPA1 Related Signaling Pathway

TRPA1 is expressed in sensory nerve endings and is involved in signal transduction of pain perception in response to a variety of stimuli, such as cold, mechanical, and chemical stimuli. Activation of TRPA1 can cause the inflow of calcium ions, leading to the depolarization of neurons and the production of pain signals. TRPA1 can be activated by a variety of inflammatory mediators, such as arachidonic acid metabolites and reactive oxygen species, which in turn release inflammatory mediators such as neuropeptides, thereby promoting the inflammatory response.

TRPA1 Related Diseases

TRPA1 is essential for nerve injury and chemotherapy-induced neuropathic pain, and it plays a role in mechanical and cold hypersensitivity reactions; TRPA1 is involved in the regulation of inflammation in chronic obstructive pulmonary disease, bronchial asthma, colitis and other inflammatory diseases. Activation of TRPA1 is associated with symptoms of irritating contact dermatitis, such as edema, pain, and neurogenic inflammation; TRPA1 has been shown to promote the transdifferentiation of myocardial fibroblasts, affect cardiovascular function, and may play a role in cardiac repair after myocardial infarction. There is also a correlation between respiratory and digestive diseases.

Bioapplications of TRPA1

Because TRPA1 plays a key role in pain perception, drugs targeting TRPA1 can be used to treat acute and chronic pain, such as postoperative pain, inflammatory pain, and neuropathic pain. An in-depth study of the structure and function of TRPA1 could help develop new, disease-specific drugs.

Case Study 1: Akihiko Sakamoto, 2023

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective ion channel implicated in thermosensation and inflammatory pain. It has been reported that expression of the TRPA1 channel is induced by cigarette smoke extract. Acrolein found in cigarette smoke is highly toxic and known as an agonist of the TRPA1 channel. However, the role of TRPA1 in the cytotoxicity of acrolein remains unclear. Here, this study investigated whether the TRPA1 channel is involved in the cytotoxicity of acrolein in human lung cancer A549 cells. The IC50 of acrolein in A549 cells was 25 μM, and acrolein toxicity increased in a concentration- and time-dependent manner. When the effect of acrolein on TRPA1 expression was examined, the expression of TRPA1 in A549 cells was increased by treatment with 50 μM acrolein for 24 h or 500 μM acrolein for 30 min. These results suggest that acrolein induces TRPA1 expression by activating these transcription factors. Overexpression of TRPA1 in A549 cells increased acrolein sensitivity and the level of protein-conjugated acrolein (PC-Acro), while knockdown of TRPA1 in A549 cells or treatment with a TRPA1 antagonist caused tolerance to acrolein. These findings suggest that acrolein induces the TRPA1 channel and that an increase in TRPA1 expression promotes the cytotoxicity of acrolein.

Fig1. TRPA1 in membrane fraction in A549 cells was measured using western blot analysis.

Fig2. Plasmids for knockdown or overexpression of TRPA1 were transfected into A549 cells.

Case Study 2: Avnika Bali, 2023

A drastic TRPA1 mutant (R919*) identified in CRAMPT syndrome patients has not been mechanistically characterized. Here, the researchers show that the R919* mutant confers hyperactivity when co-expressed with wild type (WT) TRPA1. Using functional and biochemical assays, this study revealed that the R919* mutant co-assembles with WT TRPA1 subunits into heteromeric channels in heterologous cells that are functional at the plasma membrane. The R919* mutant hyperactivates channels by enhancing agonist sensitivity and calcium permeability, which could account for the observed neuronal hypersensitivity-hyperexcitability symptoms. Postulated that R919* TRPA1 subunits contribute to heteromeric channel sensitization by altering pore architecture and lowering energetic barriers to channel activation contributed by the missing regions. The results uncover insights into the process of TRPA1 gating, and provide an impetus for genetic analysis of patients with CRAMPT or other stochastic pain syndromes.

Fig3. Expression of WT (black) or R919* (pink) hTRPA1 in the plasma membrane is represented by filled bars.

Fig4. Immunoblotting analysis of biotinylated 3×FLAG-WT hTRPA1, R919* hTRPA1, or Kv1.2/2.1 co-expressed with empty vector (mock), BioID2-WT hTRPA1, or BioID2-Kv1.2/2.1.

TRPA1 has several biochemical functions, for example, channel activity,intracellular ligand-gated calcium channel activity,temperature-gated cation channel activity. Some of the functions are cooperated with other proteins, some of the functions could acted by TRPA1 itself. We selected most functions TRPA1 had, and list some proteins which have the same functions with TRPA1. You can find most of the proteins on our site.

TRPA1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with TRPA1 here. Most of them are supplied by our site. Hope this information will be useful for your research of TRPA1.