Naturally Produced Defensive Alkenal Compounds Activate TRPA1

Abstract

(E)-2-alkenals are aldehydes containing an unsaturated bond between the alpha and beta carbons. 2-alkenals are produced by many organisms for defense against predators and secretions containing (E)-2-alkenals cause predators to stop attacking and allow the prey to escape. Chemical ecologists have described many alkenal compounds with 3-20 carbons common, having varied positions of double bonds and substitutions. How do these defensive alkenals act to deter predators? We have tested the effects of (E)-2-alkenals with 6-12 carbons on transient receptor potential channels (TRP) commonly found in sensory neurons. We find that (E)-2-alkenals activate transient receptor potential ankyrin subtype 1 (TRPA1) at low concentrations-EC50s 10-100 µM (in 0 added Ca(2+) external solutions). Other TRP channels were either weakly activated (TRPV1, TRPV3) or insensitive (TRPV2, TRPV4, TRPM8). (E)-2-alkenals may activate TRPA1 by modifying cysteine side chains. However, target cysteines include others beyond the 3 in the amino-terminus implicated in activation, as a channel with cysteines at 621, 641, 665 mutated to serine responded robustly. Related chemicals, including the aldehydes hexanal and decanal, and (E)-2-hexen-1-ol also activated TRPA1, but with weaker potency. Rat trigeminal nerve recordings and behavioral experiments showed (E)-2-hexenal was aversive. Our results suggest that TRPA1 is likely a major target of these commonly used defensive chemicals.

Electrophile-Induced Conformational Switch of the Human TRPA1 Ion Channel Detected by Mass Spectrometry

“…Recently our data from single channel recordings demonstrated that activation of purified hTRPA1 and Anopheles gambiae TRPA1 (AgTRPA1) by electrophilic compounds occurs even in the absence of all, except Cys703 in hTRPA1, intracellular N-terminal cysteines [ 9 , 14 ]. In line with our findings, other groups have shown that some electrophiles, including p -benzoquinone, polygodial, isovalleral and (E)-2 alkenals, robustly activated heterologously expressed TRPA1 lacking three of the N-terminal critical cysteines (Cys621, Cys641 and Cys665) [ 15 , 16 , 17 ]. Knowing the reactivity of each cysteine in hTRPA1 to electrophilic compounds is crucial for understanding their biological role and may facilitate the development of new therapeutics for relief of pain.…”

“…When exposed to oxidants, additional disulphide bonds may appear [ 8 ] that could further change the protein conformation as well as the binding pattern of electrophilic compounds such as NMM. Although Cys621 and Cys665 may not always be the starting point of electrophile TRPA1 activation [ 9 , 15 , 16 , 17 , 25 ], these cysteines stand out as central in the formation of the TRPA1 N-terminal ARD disulphide network [ 8 , 11 , 20 , 24 , 25 ]. Indeed, in our experiments, no NMM adducts were observed to Cys621 and relatively little NMM labeling was observed to Cys665, which is consistent with their central role in a disulphide network.…”

TRPA1 channels: molecular sentinels of cellular stress and tissue damage

“…TRPA1 activators include ( E )‐2‐alkenals, aldehydes containing an unsaturated bond between the α and β carbons, produced by many animals for chemical deterrence (Blair et al . ). The list of industrial electrophiles acting on TRPA1 is huge and includes aldehydes (e.g.…”

Benzoquinones in the defensive secretion of a bug (Pamillia behrensii): a common chemical trait retrieved in the Heteroptera

“…Like other chemicals, benzoquinones activate the transient receptor potential ankyrin 1 (TRPA1), a nonselective cation channel, which has a conserved function as a noxious chemical receptor in animals (Arenas et al 2017; Ibarra and Blair 2013). TRPA1 might thus be a major target of many convergently evolved defensive chemicals like benzoquinones and initiate protective behavior after a chemical attack (Blair et al 2016; Ibarra and Blair 2013).…”