TRPA1 channels: molecular sentinels of cellular stress and tissue damage

Abstract

TRPA1 is a non‐selective cation channel expressed in mammalian peripheral pain receptors, with a major role in chemonociception. TRPA1 has also been implicated in noxious cold and mechanical pain sensation. TRPA1 has an ancient origin and plays important functions in lower organisms, including thermotaxis, mechanotransduction and modulation of lifespan. Here we highlight the role of TRPA1 as a multipurpose sensor of harmful signals, including toxic bacterial products and UV light, and as a sensor of stress and tissue damage. Sensing roles span beyond the peripheral nervous system to include major barrier tissues: gut, skin and lung. Tissue injury, environmental irritants and microbial pathogens are danger signals that can threaten the health of organisms. These signals lead to the coordinated activation of the nociceptive and the innate immune system to provide a homeostatic response trying to re‐establish physiological conditions including tissue repair. Activation of TRPA1 participates in protective neuroimmune interactions at multiple levels, sensing ROS and bacterial products and triggering the release of neuropeptides. However, an exaggerated response to danger signals is maladaptive and can lead to the development of chronic inflammatory conditions.

Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies

“…Similarly, acidic pH has also been shown to activate TRPA1 in a species-dependent manner; human, but not rodent TRPA1 is sensitive to acidic pH [60], and a dose-dependent increase in channel gating was found for increasing proton concentration associated with CO 2 or other weak organic acids [61,62]. ROS, a redox mediator released during injury/inflammation activates TRPA1 via cysteine oxidation or formation of disulphide bonds between cysteine residues in the channel protein [63,64,65]. Furthermore, it has been suggested that ROS-mediated lipid peroxidation leads to 4-hydroxynonenal (4-HNE) production, which then covalently modifies the cytoplasmic cysteine residues to activate TRPA1 [64,66].…”

“…Furthermore, it has been suggested that ROS-mediated lipid peroxidation leads to 4-hydroxynonenal (4-HNE) production, which then covalently modifies the cytoplasmic cysteine residues to activate TRPA1 [64,66]. Reactive nitrogen species have also been shown to activate the channel by S-nitrosylation [63,64,65,67]. In addition to nitric oxide (NO), another “gasotransmitter”, hydrogen sulphide (H 2 S), has also been suggested to activate TRPA1 channel [68,69].…”

Transient Receptor Potential Ankyrin 1 and Substance P Mediate the Development of Gastric Mucosal Lesions in a Water Immersion Restraint Stress Rat Model

“…Moreover, TRPA1 plays a major role in mediating visceral pain in mice [28] and is also closely related to gastric mucosal injury. Recent studies have described the role of TRPA1 in inflammatory and neuropathic pain [27]. Based on the abovementioned results, we wanted to know whether the release of SP is related to TRPA1 from primary afferent fibers during stress.…”

“…TRPA1 is also expressed in SP-positive neurons in the DRG and stomach of rats. The predominance of TRPA1 and SP co-expression in the DRG and stomach of rats probably indicates frequent interaction of SP and TRPA1 [27]. Moreover, TRPA1 plays a major role in mediating visceral pain in mice [28] and is also closely related to gastric mucosal injury.…”

Hydrogen Peroxide Induces Muscle Nociception via Transient Receptor Potential Ankyrin 1 Receptors

“…13–15 TRPA1 is expressed in small-and medium-sized nociceptive neurons of the dorsal root, trigeminal and nodose ganglia and TRPA1 antagonists have been studied as analgesic drugs. 13 We recently demonstrated that the TRPA1 antagonist HC-030031 inhibited guarding behavior after plantar incision but did not affect exaggerated heat or mechanical responses.…”