Analysis of Drosophila TRPA1 reveals an ancient origin for human chemical nociception

Abstract

Chemical nociception, the detection of tissue-damaging chemicals, is important for animal survival and causes human pain and inflammation, but its evolutionary origins are largely unknown. Reactive electrophiles are a class of noxious compounds humans find pungent and irritating, like allyl isothiocyanate (in wasabi) and acrolein (in cigarette smoke)1–3. Insects to humans find reactive electrophiles aversive1–3, but whether this reflects conservation of an ancient sensory modality has been unclear. Here we identify the molecular basis of reactive electrophile detection in flies. We demonstrate that dTRPA1, the Drosophila melanogaster ortholog of the human irritant sensor, acts in gustatory chemosensors to inhibit reactive electrophile ingestion. We show that fly and mosquito TRPA1 orthologs are molecular sensors of electrophiles, using a mechanism conserved with vertebrate TRPA1s. Phylogenetic analyses indicate invertebrate and vertebrate TRPA1s share a common ancestor that possessed critical characteristics required for electrophile detection. These findings support emergence of TRPA1-based electrophile detection in a common bilaterian ancestor, with widespread conservation throughout vertebrate and invertebrate evolution. Such conservation contrasts with the evolutionary divergence of canonical olfactory and gustatory receptors and may relate to electrophile toxicity. We propose human pain perception relies on an ancient chemical sensor conserved across ~500 million years of animal evolution.

Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli

“…3C) or properties of native rat snake TRPA1, which exhibits low heat and moderate AITC sensitivity (10). Indeed, this inverse relationship between thermosensitivity and chemosensitivity also pertains to invertebrate (insect) orthologs (10,12), suggesting an ancient arrangement in TRPA1 structures that has been maintained over a long evolutionary period and in the face of extensive drift in primary amino acid sequence (Drosophila and human TRPA1 share <30% sequence identity). Unlike TRPA1, TRPV1 is heat-sensitive in all vertebrate species thus far examined.…”

“…Recent studies of the capsaicin receptor, TRPV1, suggest that the N-terminal ARD constitutes a binding site for cytoplasmic regulatory factors, such as ATP and calmodulin (17,45), consistent with our findings that the TRPA1 ARD contributes to channel modulation by environmental and endogenous agents. Several TRP channels act as polymodal signal detectors (5, 46), but TRPA1 is unique in that different species use this channel for distinct physiological purposes, generally favoring one modality (thermal or chemical) over the other (10,12). This may reflect evolutionary pressure to reduce background noise from environmental irritants in organisms in which the channel is used primarily for thermoreception, and vice versa.…”

“…For example, snakes are unique among vertebrates in that their TRPA1 channels are heat-sensitive, which some species (rattlesnakes, boas, and pythons) have exploited to detect infrared radiation (10). Similarly, insect TRPA1 channels are heat-sensitive and contribute to thermal avoidance behaviors (11)(12)(13)(14). In these cases, however, thermosensitivity comes at the expense of chemosensitivity, such that AITC and other chemical irritants still activate these channels but with reduced potency compared with mammalian orthologs (10).…”

Redox regulation of calcium ion channels: Chemical and physiological aspects

“…In a parallel study, Macpherson et al [121] used click chemistry and mass spectrometry to identify 14 cysteines that can be modified by iodoacetamide (IA); three of which (C415, C422 and C622, mouse TRPA1) are critical for mediating the activating effect of mustard oil on channel function. Cysteine 622 (mTRPA1) is identical to C621 (hTRPA1) and is conserved in TRPA1 clade members with the exception of Ciona intestinales, as also C622, C415, C422, C642 and K712 (mTRPA1), suggesting an ancient shared origin of chemical nociception [122].…”

Drosophila TRPA1 isoforms detect UV light via photochemical production of H 2 O 2

“…Indeed, a recent finding has suggested that two specific GPCRs-GUR-3 and LITE-1-both of which play important roles in light sensing in C. elegans, may also be H 2 O 2 sensitive (16). Moreover, TRPA1, an evolutionarily conserved TRP channel known for its role in sensing many chemical irritants, has been shown to sense H 2 O 2 (17)(18)(19)(20)(21)(22)(23)(24), thus TRPA1 may be activated by light via sensing light-induced H 2 O 2 production. Some recent evidence has demonstrated a role for TRPA1 in light sensing.…”