Trpa1

Official Full Name

transient receptor potential cation channel, subfamily A, member 1

Organism

Mus musculus

GeneID

277328

Background

Enables calcium channel activity. Involved in cell surface receptor signaling pathway; detection of mechanical stimulus involved in sensory perception; and response to organic cyclic compound. Acts upstream of or within several processes, including detection of stimulus involved in sensory perception of pain; response to hydrogen peroxide; and thermoception. Located in stereocilium bundle. Is expressed in cochlea; dorsal root ganglion; glossopharyngeal ganglion; and lumbar dorsal root ganglion. Human ortholog(s) of this gene implicated in familial episodic pain syndrome 1. Orthologous to human TRPA1 (transient receptor potential cation channel subfamily A member 1). [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

Trpa1; Anktm1; TRPA1b;

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Detailed Information

The superfamily of Transient Receptor Potential (TRP) cation channels consists of unique proteins, which are expressed in almost every cell type and play key roles in various homeostatic functions. As sensors of chemical and thermal stimuli, TRP ion channels have crucial roles in somatosensation. One of the members of this family, TRPA1, is expressed by primary afferent nociceptors in mammals, where it detects structurally diverse noxious compounds that cause pain and neurogenic inflammation. Such activators include pungent irritants from onion, mustard and garlic, as well as volatile environmental toxins and endogenous pro-algesic agents. TRPA1 is also activated downstream of phospholipase-C-coupled receptors and has been considered to function as a sensor of noxious cold. TRPA1 is associated with persistent pain, respiratory and chronic itch syndromes and is therefore a promising target for treating these and other neurogenic inflammation.

TRPA1 in Pain and Inflammation

The sensation of pain is caused by somatosensory stimuli producing a cascade of adaptive responses in the body. This sensation involves complex interactions between specialized nerves, the brain and the spinal cord. The detection of painful mechanical, chemical or thermal stimuli is due to the activation of nociceptors present in the primary afferent nerve fibers of the somatosensory system. Experiments in the skin show that chemical activation of TRPA1 produces heat sensation and mechanical hyperalgesia, pain, cold hyperalgesia and a neurogenic axon reflex erythema. Sustained activation of TRPA1 by endogenous agonists implicates this channel in persistent and chronic pain in a wide variety of conditions, such as inflammation, osteoarthritis, neuropathy, migraine, fibromyalgia, diabetes, emphysema and bronchitis and thus may be an ideal target for novel analgesic and anti-inflammatory molecules.

Figure 1. Activation and sensitization of TRPA1 by inflammatory mediators. (Talavera K, et al., 2020)

TRPA1 in Cardiovascular Diseases

The application of TRPA1 agonists leads to dilation of several arteries and these responses are smaller when the vessels are treated with TRPA1 blockers or in preparations isolated from Trpa1 deficient mice. It has found that TRPA1 activation in sensory nerves induces the release of Calcitonin gene-related peptide (CGRP), which then binds to its G protein-coupled receptor expressed on the vascular smooth muscle cells (VSMC) membrane, resulting in myocyte hyperpolarization and relaxation. Alternatively, the Ca²⁺ influx via TRPA1 activation in endothelial cells may cause VSMC relaxation and vasodilation. In this regard, it should be noted that TRPA1 expression is abundant in the endothelial cell plasma membrane that is in proximal contact with VSMC. These junctions host the cellular signaling players necessary for endothelium-dependent VSMC hyperpolarization and vasodilation, such as Ca²⁺-activated K+ channels (KCa) and myo-endothelial gap junctions. The activation of TRPA1 (by AITC) in endothelial cells induces Ca²⁺ influx and vasodilation of pressurized rat cranial vessels.

TRPA1 Antagonists in Drug Discovery

TRPA1 antagonists include a wide range of organic and inorganic chemicals characterized by heterogeneous chemotypes. Ruthenium red, amiloride, gentamicin, and gadolinium were recognized among the first blockers of the TRPA1 channel, even though nonspecific over other ion channels. Recent advances in this area resulted in the identification of more selective TRPA1 antagonists that have been optimized with regard to drug-like properties. The xanthine derivative known as HC030031 can be considered the parent compound of most of the newer TRPA1 antagonists. The compound showed high selectivity for TRPA1 over almost 50 different targets involved in pain transmission, including enzymes, receptors and transporters. HC030031 is widely used as a typical TRPA1 antagonist and its employment as a pharmacological tool largely contributed to the validation of the channel as a drug target in multiple therapeutic areas.

TRPA1 is a final common pathway for many pronociceptive agonists generated in various pathophysiological pain conditions, and so it is a promising pain treatment target. In experimental animal studies, blocking TRPA1 has effectively attenuated pain behavior in many pathophysiological pain conditions. According to whether the TRPA1-mediated pronociception is due to enhanced transduction in the periphery, amplification of transmission centrally or both, pain treatment with a TRPA1 antagonist requires a compound that acts peripherally and/or centrally.

References:

Talavera K, et al. Mammalian transient receptor potential TRPA1 channels: from structure to disease. Physiological Reviews, 2020, 100(2): 725-803.
Paulsen C E, et al. Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature, 2015, 520(7548): 511-517.
Nassini R, et al. The TRPA1 channel in inflammatory and neuropathic pain and migraine. Reviews of Physiology, Biochemistry and Pharmacology, Vol. 167. Springer, Cham, 2014: 1-43.
Preti D, et al. Transient receptor potential ankyrin 1 (TRPA1) antagonists. Pharmaceutical Patent Analyst, 2015, 4(2): 75-94.
Koivisto A, et al. TRPA1 antagonists for pain relief. Pharmaceuticals, 2018, 11(4): 117.

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