Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control

Abstract

New studies have revealed an essential role for TRPA1, a sensory neuronal TRP ion channel, in airway chemosensation and inflammation. TRPA1 is activated by chlorine, reactive oxygen species, and noxious constituents of smoke and smog, initiating irritation and airway reflex responses. Together with TRPV1, the capsaicin receptor, TRPA1 may contribute to chemical hypersensitivity, chronic cough, and airway inflammation in asthma, COPD, and reactive airway dysfunction syndrome.

Figure 1. Structures of TRPA1 and TRPV1 with ligand interaction and regulatory sites

Structures of TRPA1 (left) and TRPV1 (right) monomers, modeled after the X-ray crystal structure of the potassium channel, Kv1.2, a channel of the same superfamily of P-loop cation channels (77). The intracellular N-terminal segment of TRPA1 has ∼ 15 ankyrin repeats, containing several cysteine and lysine residues (grey) crucial for activation by reactive agonists, as well as a partial EF-hand domain implicated in calcium-dependent gating (39, 50, 80, 138). Sites in transmembrane domain S6 are essential for gating by antagonists and agonists (31). TRPV1 is gated by vanilloids and endogenous inflammatory fatty acid metabolites binding to sites close to the intracellular face of the membrane (58). Protons interact with sites at the extracellular end of S5 and within the channel pore loop (59). N- and C-termini have interaction sites for calmodulin (CaM) and ATP (127). Positively charge domains within the C-termini of TRPA1 and TRPV1 may serve as interaction sites for phosphatidylinositol-4,5-bisphosphate (PIP₂), the substrate of phospholipase C, exerting an inhibitory effect on channel function (36, 62, 105, 127).

Figure 2. Chemical irritants activating TRPA1 through reactive mechanisms

TRPA1 is activated by a large variety of reactive irritants, including acrolein, a major constituent of tobacco smoke, allicin, mustard oil and cinnamaldehyde, the pungent ingredients in garlic mustard and cinnamon, respectively, chlorobenzylidene malononitrile (CS tear gas), the reactive oxygen species (ROS) hydrogen peroxide and hydroxyl radical, and hypochlorite, the product of the potent irritant gas, chlorine. Formaldehyde is a potent industrial and environmental irritant. Isovelleral, a painful fungal dialdehyde sesquiterpene, activates TRPA1 to deter fungivores. TRPA1 is also activated by the disinfectant, chloramines-T, as well as by 4-hydroxy-nonenal (4-HNE), a potential endogenous agonist. Reactive irritants activate TRPA1 through covalent protein modification, as shown for the example of acrolein undergoing a Michael addition reaction with a cysteine residue. Oxidants such as hypochlorite or hydrogen peroxide oxidize cysteine residues to sulfinic or sulfonic acid groups.

Figure 3. Sensitization and activation of sensory neuronal TRP ion channels by inflammatory signaling pathways

TRPA1 and TRPV1 are sensitized or activated through multiple phospholipase C-coupled receptor pathways active during inflammation, including receptors for histamine, bradykinin, prostaglandins, proteases, nerve growth factor. Intracellular Ca²⁺ is crucial for activation of TRPA1, mobilized either through release from intracellular stores, permeation through TRPA1, or, possibly, TRPV1. Phosphorylation through PKC and other kinases also affect TRP channel activity during inflammation. Heightened Ca²⁺ levels trigger release of pro-inflammatory neuropeptides such as substance p or CGRP.