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Review
. 2016 Aug 1;594(15):4151-69.
doi: 10.1113/JP270935.

TRPA1 channels: molecular sentinels of cellular stress and tissue damage

Félix Viana  1
Affiliations
Review

TRPA1 channels: molecular sentinels of cellular stress and tissue damage

Félix Viana. J Physiol. .

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.

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Figures

Figure 1
Figure 1. Cryo‐EM structure of human TRPA1
A, schematic topology of two TRPA1 subunits based on the cryo‐EM images with relevant functional regions shown in different colours. Ankyrin repeats (turquoise), pre‐S1 linker (orange), S1–S4 (magenta), S5–S6 (blue), gate residues (orange), TRP‐domain helix (red) and C‐terminus coiled coil (green). The antagonist A‐967079 is represented as a green circle and the S4–S5 pocket is marked with a green asterisk. Cysteines essential for response to reactive electrophiles (black circles); myo‐inositol hexakisphosphate (IP6) (grey hexagon). The position of the misense mutation N855S causing familial episodic pain syndrome is shown by the white star and the polymorphisms E179K causing reduced paradoxical heat sensation by the blue triangle. The N‐terminus and ankyrin repeats 1–11, which are missing from the TRPA1 structure, are shown in grey. Curved black lines denote the suspected flexibility of the linkage between 1–11 and the remaining ankyrin repeats. Potential interactions between the N‐terminus and the membrane or membrane‐associated factors are indicated by a black arrow. Intracellular mutations reported to disturb calcium‐dependent potentiation or inactivation of TRPA1 are marked with red diamonds. This figure, slightly modified from the original, is reprinted from Brewster & Gaudet (2015) with permission. B, ribbon and schematic diagram of human TRPA1 atomic model for residues Lys 446–Thr 1078 (Protein Data Bank entry 3J9P) viewed from the membrane plane. Only two subunits are presented, following the same colour scheme as in A. Residue F909 (green circle) interacts with the antagonist A‐967079. Also shown are the locations of Cys 621 and 641 and Asn 855. C, schematic diagram of four TRPA1 subunits (each colour‐coded) viewed from the extracellular face. D, same view of the surface with one the subunits partially visible to illustrate the domain‐swapping of the S1–S4 bundle (lateral) and the pore‐forming S5–S6 (medial) region.
Figure 2
Figure 2. Amino acid sequence of human TRPA1
Each TRPA1 subunit (1119 amino acid residues) has a long intracellular NH2 terminus (719 amino acids) characterized by multiple ankyrin domains, six transmembrane domains (S1–S6) and a shorter intracellular C‐terminus. The figure highlights (colour coded) residues involved in TRPA1 function, including genetic variants linked to increased and decreased channel activity. Some residues important for AITC sensitivity are also involved in responses to other electrophilic agonists.
Figure 3
Figure 3. TRPA1 is a sensor of danger signals in neuronal and non‐neuronal tissues
TRPA is expressed in peptidergic sensory nerve terminals and in different barrier tissues (e.g. skin keratinocytes, vascular endothelium). TRPA1 is activated by exogenous danger signals, including UV radiation, chemical irritants, bacterial products, mechanical forces and extreme temperatures. In addition, tissue damage releases intracellular alarmins such as ATP and uric acid that can signal to resident macrophages and extravasating monocytes. TRPA1 activation depolarizes nociceptor terminals sending pain signals to the CNS. The local calcium influx releases neuropeptides (e.g. substance P (SP) and CGRP) that act on the vasculature producing vasodilatation. In the brain, vasodilatation is linked to the opening of Ca2+‐activated potassium channels. Toxic bacterial products, including LPS, have rapid excitatory effects on TRPA1‐expressing terminals. Inflammatory mediators act on membrane receptors (GPCRs, cytokines, TLRs) to sensitize nociceptive channels including TRPA1, resulting in further amplification of danger signals. TRPA1 is also activated by ROS and RNS.
Figure 4
Figure 4. Role of TRPA1 channels in neuroimmune interactions
Non‐neuronal and nociceptor TRPA1 channels respond to a very broad range of danger signals, including many molecules that activate host immunity. Listed in blue at the top of the figure are molecules for which a direct or indirect activation of TRPA1 has been demonstrated. Activation of immune cells releases inflammatory mediators that in many cases lead to sensitization of TRPA1‐expressing nociceptors. This positive feedback loop can be further potentiated by the release of neuropeptides (SP, CGRP, etc.) from peptidergic nociceptors. The combined activation of the nociceptive and the immune system results in behavioural, vascular and tissue responses (listed in green) that minimize damage and promote repair. Alteration in the homeostatic balance between the nociceptive and the immune system can reinforce the response to danger signals, resulting in different chronic diseases. Inhibitors of TRPA1 activity (listed in orange) can minimize the response to danger signals exerting a negative bias against the exacerbation of inflammation and reducing pain.
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