- The Transient Receptor Potential Ankyrin (TRPA) channel subfamily is one of the most structurally distinct and functionally specialized groups within the TRP superfamily. In mammals, the subfamily contains a single member, TRPA1, which plays a prominent role in sensing environmental irritants, chemical stimuli, and noxious cold.
- TRPA1 is a non-selective cation channel permeable to calcium (Ca²⁺) and sodium (Na⁺), and it is widely expressed in sensory neurons, particularly nociceptors—the pain-sensing neurons of the dorsal root, trigeminal, and nodose ganglia. It acts as a molecular sensor of potentially harmful stimuli and contributes significantly to inflammatory pain, neuropathic pain, and respiratory irritation.
- Structurally, TRPA1 is characterized by the presence of multiple ankyrin repeat domains (up to 16) in its N-terminal region, which is a defining feature of this subfamily. These ankyrin repeats are thought to mediate protein–protein interactions and may contribute to the channel’s sensitivity to mechanical and chemical stress. Like other TRP channels, TRPA1 has six transmembrane segments with a pore-forming loop between the fifth and sixth segments and cytoplasmic N- and C-terminal domains that are involved in regulatory interactions.
- Functionally, TRPA1 is a polymodal sensor—it can be activated by a broad range of physical and chemical stimuli. It is best known for its sensitivity to reactive electrophilic compounds, such as allyl isothiocyanate (found in mustard oil), cinnamaldehyde (from cinnamon), allicin (from garlic), and acrolein (a component of smoke and pollutants). These compounds covalently modify cysteine residues in the N-terminal domain of the channel, triggering its activation. TRPA1 is also activated by cold temperatures (below ~17°C), although this feature is still debated and may be species-specific. Furthermore, TRPA1 responds to mechanical stretch and intracellular calcium, contributing to its function in mechanosensation and pain amplification.
- In addition to its role in sensory neurons, TRPA1 is also found in various non-neuronal tissues, including the respiratory tract, gastrointestinal tract, cardiovascular system, and immune cells. In the airways, TRPA1 contributes to cough reflexes, asthma, and airway inflammation by detecting inhaled irritants and triggering protective responses. In the gut, it may play a role in motility and visceral pain. In vascular tissues, TRPA1 can influence vasodilation and blood pressure regulation through endothelial signaling.
- Clinically, TRPA1 is a major target for the development of analgesic and anti-inflammatory drugs, particularly for chronic pain conditions. Because it is involved in both the detection of harmful stimuli and the maintenance of inflammation-induced hypersensitivity, blocking TRPA1 function has the potential to alleviate pain without affecting normal touch or temperature sensation. Moreover, its role in detecting environmental irritants makes it a potential target for treating respiratory diseases such as chronic cough, asthma, and chronic obstructive pulmonary disease (COPD).
