Pflugers Arch - Eur J Physiol (2012) 464:425–458
DOI 10.1007/s00424-012-1158-z
INVITED REVIEW
The transient receptor potential channel TRPA1: from gene
to pathophysiology
Bernd Nilius & Giovanni Appendino & Grzegorz Owsianik
Received: 4 September 2012 / Revised: 6 September 2012 / Accepted: 6 September 2012 / Published online: 22 September 2012
# Springer-Verlag 2012
Abstract The Transient Receptor Potential Ankyrin 1 chan-
nel (TRPA1), is a member of the large TRP family of ion
channels, and functions as a Ca2+ permeable non-selective
cation channel in many different cell processes, ranging
from sensory to homeostatic tasks. TRPA1 is highly con-
served across the animal kingdom. The only mammalian
TRPA subfamily member, TRPA1, is widely expressed in
neuronal (e.g. sensory dorsal root and trigeminal ganglia
neurons)- and in non-neuronal cells (e.g. epithelial cells,
hair cells). It exhibits 14–19 amino-(N-)terminal ankyrin
repeats, an unusual structural feature. The TRPA1 channel
is activated by noxious cold (<17 °C) as well as by a
plethora of chemical compounds that includes not only
electrophilic compounds and oxidants that can modify, in
an alkylative or oxidative fashion, nucleophilic cysteine
residues in the channel’s N-terminus, but also compounds
that do not covalently bind to the channel proteins (e.g.
menthol, nifedipin). Based on localization and functional
properties, TRPA1 is considered a key player in acute and
chronic (neuropathic) pain and inflammation. Moreover, its
role in the (patho)physiology of nearly all organ systems is
anticipated, and will be discussed along with the potential of
TRPA1 as a drug target for the management of various
pathological conditions.
B. Nilius (*) : G. Owsianik
Department of Cellular and Molecular Medicine,
Laboratory Ion Channel Research, KU Leuven,
Campus Gasthuisberg,
3000 Leuven, Belgium
e-mail: Bernd.Nilius@med.kuleuven.be
G. Appendino
Dipartimento di Scienze Chimiche Alimentari,
Farmaceutiche e Farmacologiche,
Novara, Italy
Keywords Transient receptor potential . Ca2+ channels .
Ankyrin repeat domain . Nociception . Mechano-sensing .
Channeloparthies
Introduction
The superfamily of Transient Receptor Potential (TRP) cat-
ion channels comprises unique sensory proteins that are
expressed in almost every tissue and cell type, and that play
an important role in diverse homeostatic functions. TRP
channels are organized into seven subfamilies: the TRPC
(‘Canonical’), TRPV (‘Vanilloid’), TRPM (‘Melastatin’),
TRPP (‘Polycystin’), TRPML (‘Mucolipin’), the TRPA
(‘Ankyrin’), and TRPN (‘NOMP-C’) (for reviews see [58,
100, 210, 304]). One member of the TRP family, the
ankyrin-repeat channel TRPA1 is of special interest for its
functional diversity as a sensor of irritating and cell damag-
ing signals, and its important role in many different diseases.
This review aims at providing a comprehensive review of
our current knowledge on structure, function and druggabil-
ity of this fascinating ion channel.
The trpa1 gene
The trpa1 gene was originally cloned from lung fibroblasts
in 1999 [128]. It was originally baptized ANKTM1 as it
contains multiple ankyrin repeats in the amino-(N-) terminal
part [260]. The human trpa1 gene is composed of 27 exons
and spans 55,701 base pairs (bp) of the human chromosome
8q13. It has been also found in many vertebrates and inver-
tebrates, including mouse, rat dog, chicken, zebrafish, fruit
fly and Caenorhabditis elegans. In contrast to mammals that
contain only one trpa1 gene, other classes of the Animalia
Kingdom contain multiple TRPA1 homologues (e.g. 4 in
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fruit fly, 2 in C.elegans, 2 in zebrafish, 4 in sea squirt Ciona
intestinalis). It is believed that all animals contain at least
one trpa1 gene.
There is an evolutionary link among electrophile-sensitive
TRPA1s across species. Interestingly, the phylogenetic trees
of TRPA proteins indicated a clear separation of electrophile-
sensitive TRPA1s and electrophile-insensitive (or basal)
TRPAs. All electrophile-sensitive TRPA1s derive from a com-
mon ancestor of both vertebrates and invertebrates. Therefore,
it can be considered that the function of TRPA1 has been
conserved for ~500 millions of years [133, 175] (Fig. 1).
Protein structure
The trpa1 gene encodes a ~1,100 amino acid (aa) protein
of ~120–130 kDa (e.g. 1,119 aa in human, 1,125 aa in rat,
1,115 aa in mouse, 1,120 aa in zebrafish, 1,197 aa in fruit fly,
1,193 aa in C. elegans). In addition to full length protein
versions, shorter splice variants have also been identified.
Similarly to other TRP channels, TRPA1 very likely functions
as a homotetramer composed of TRPA1 proteins [208, 211].
(see also Fig. 2).
The predicted structural topology of TRPA1 is similar to
other TRP proteins and comprises six putative transmem-
brane segments (S1-6). The putative ion permeable site
(pore, pore helix and selectivity filter) is located between
S5-S6 and the first extracellular loop between S1-S2 con-
tains 2 putative Asn-glycosylation sites. The long N-terminal
moiety contains up to 18 ankyrin repeat domains (ARDs)
composed of 33 aa that might be involved in protein-protein
interactions as well as in channel trafficking to the plasma
membrane. Deletions of TRPA1 ARDs were shown, in fact, to
negatively affect the insertion of the channel into the plasma
membrane [211]. Recently, it has been shown in a model of
Fig. 1 Bayesian consensus
phylogeny of TRPA channels.
Red dot denotes ancestor of
TRPA1 clade (adapted from
[132] with permission)
Pflugers Arch - Eur J Physiol (2012) 464:425–458
TRPA1 with 17 ankyrin repeats (AR), that Ca2+ binding to the
ARD changes the overall structure of the N-terminus, increas-
ing its stiffness and diminishing its end-to-end distance. In the
transmembrane domain of TRPA1, N855, the important resi-
due close to TM5 and associated with familial episodic pain
syndrome, forms a strong link between the S4-S5 connecting
helix and S1, thereby creating a direct force link between the
N-terminus and the gate [318].
The putative EF hand motive involved in intracellular
Ca2+ ([Ca2+]i)-dependent activation of TRPA1 is located
between ARD11 and ARD12 [72, 325]. The importance of
this EF hand site is questionable, since point mutations in
this region have only modest effects on [Ca2+]i-dependent
activation mechanism, while deletions impair trafficking of
the truncated channel to the plasma membrane [211].
Another putative Ca2+ -binding domain is composed of a
cluster of acidic residues in the distal carboxy-(C-)terminus
of TRPA1 [265]. Four conserved residues in human TRPA1,
Glu1077, Asp1080, Asp1081 and Asp1082, have strong
effects on the Ca2+ - and voltage-dependent potentiation
and/or inactivation of agonist-induced responses. Truncation
of the C-terminus by only 20 residues selectively slowed down
the Ca2+ -dependent inactivation without affecting other func-
tional parameters. This acid cluster, wich shows partial homol-
ogy to the Ca binding bowl in BKCa channels, may represent
the long-sought Ca2+ -sensing domain [265].
The only direct structural insights on TRPA1 channel are
those available from a 16 Å resolution structure of purified,
amphipol-stabilized,TRPA1 proteins analyzed by single-
particle electron microscopy (EM) [62]. This structural
model suggests that the critical N-terminal cysteine residues
involved in electrophilic activation are located at the inter-
face between neighboring subunits and form a ligand-binding
pocket, allowing disulfide bonding between the cysteine res-
idues [290]. Covalent modifications by thiol-reactive
Pflugers Arch - Eur J Physiol (2012) 464:425–458
Fig. 2 Predicted structural
topology of human TRPA1
channel. a Positions of major
domains and motifs are
annotated. b Schematic
representation of a TRPA1
dimer with annotations of all 31
cysteine residues (blue circles).
The position of ankyrin repeat
domains is represented by a
gray box. c reconstruction of
electron microscopy density
and N-terminal model of
TRPA1 (blue ribbon). The cys-
teines involved in disulfide
bonding are displayed in orange
(adapted form [62, 211] with
permission)
compounds within such pockets may alter interactions
between subunits and promote conformational changes that
translate to modification of the gating mechanism [62,
290]
TRPA1 expression
Originally, TRPA1 was described as a nociceptive channel
expressed in sensory neurons of dorsal root ganglia (DRG),
trigeminal ganglia (TG), and nodose ganglia and responding
to noxious cold and pungent compounds, as well as a
putative transduction channel found in the inner ear (the
organ of Corti) and involved in hearing [24, 197, 260].
However, growing evidence suggests that TRPA1 is a
widely expressed channel present in many organs and tis-
sues, including brain, heart, small intestine, lung, skeletal
muscle, and pancreas [259].
Sensory neurons, sensory and peripheral nervous systems
In TG, TRPA1 is expressed in unmyelinated (C) and small
myelinated (Aδ) axons, with only occasional identification in
large myelinated axons. More than 25 % of TRPA1 containing
neurons are peptidergic and release substance P and calcitonin
gene-related peptide (CGRP), while the remaining neurons
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were identified as non-peptidergic neurons by isolectin B4
(IB4; ~45 %). Trigeminal sensory nuclei (TSN) and the spinal
dorsal horn (DH) are immunopositive for TRPA1. High
expression can be found in terminals of the superficial laminae
of the trigeminal caudal nucleus (Vc) and DH. Neurons in Vc
respond to intraoral cooling and TRPA1 agonists, receiving
inputs from TRPM8, TRPA1 and/or TRPV1-containing pri-
mary trigeminal afferents [85, 317].
The TRPA1 terminals, characterized by clear round
vesicles, are presynaptic to one or two dendrites, with a
small degree of synaptic divergence and little presynaptic
modulation. Occasionally, TRPA1 is also observed in post-
synaptic dendrites [143]. In the spinal cord, the substantia
gelatinosa (SG) is a key site for integration of noxious
inputs. TRPA1 is involved in the spontaneous glutamatergic
excitatory transmission in substantia gelatinosa (SG; lamina
II) [124]. Presynapticaly located TRPA1 channels increase
glutamate release, triggering synaptic transmission onto SG
neurons and evoking excitatory postsynaptic potentials
(EPSCs) in vertical- and radial-, but not islet or central SG
cells [284]. TRPA1 is involved in the presynaptic glyciner-
gic neurotransmission in the dorsal horn [54]. Moreover,
TRPA1 is also localized presynaptically in terminals of
primary afferents that innervate spinal inhibitory gamma-
aminobutyric acid (GABA) neurons, which make contacts
with SG neurons [155].
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TRPA1 is also expressed in the autonomic nervous sys-
tem. Sympathetic superior cervical ganglia (SCG) contain a
population of cold sensitive neurons that express TRPA1
[256]. TRPA1 is also present in the majority of the nodose
(placodes-derived)- and jugular (neural crest-derived)
esophageal nociceptors [42] that sense esophageal disten-
tion and respond to chemical perfusion. Bradykinin acti-
vates most nodose and all jugular C fibers via a TRPA1
dependent mechanism [150, 315].
In vagal fibers innervating the heart, TRPA1 contributes
to vasovagal reflexes [230], whereas TRPA1 activation in
vagal sensory nerves innervating the airways provides
responses to environmental stimuli, eliciting action potential
discharge in airway afferent C-fibers and the consequent
nocifensor reflexes [202, 279]. Similarly, nasal TG nerve
endings are particularly sensitive to oxidants formed in
polluted air and during oxidative stress as well as to chlorine
that is frequently released in industrial and domestic acci-
dents [30]. In general, TRPA1 is primarily expressed in
small-diameter, nociceptive neurons of primary sensory
afferent nerves innervating the whole respiratory tract [9,
26, 29, 324].
TRPA1 is highly expressed in neurons of the pelvic nerve
(PN) that innervate colon. Axons of these neurons arise
from DRG at thoracolumbar (TL) and lumbosacral (LS)
spinal levels [162]. A similar expression level was also
observed in inhibitory enteric neurons in the cecum and
the colon. Inhibitory motoneurons and descending inter-
neurons, cholinergic neurons, and intrinsic primary afferent
neurons display lower TRPA1 expression levels. The acti-
vation of TRPA1 in these neurons inhibits contractility in
the colon but not in the stomach or the small intestine and is
involved in inhibition of spontaneous neurogenic contrac-
tions [229].
In primary sensory neurons of the lumbosacral plexus
innervating the bladder (DRG level L6-S1 DRG), TRPA1
expression is linked with the bladder afferent transduction,
causing hyperreflexia through C-fiber-mediated afferent
pathway [6, 76].
In prostate, TRPA1 is located on nerves that are positive for
CB1, CB2, CGRP, nitric oxide synthase (NOS), or vesicular
acetylcholine transporter (VAChT). It has been proposed that
TRPA1 together with CB receptors may function as mediator
of mechanoafferent signals, epithelial homeostasis, emission,
or inflammation of the human prostate [108].
Central nervous system
The TRPA1 expression is clearly demonstrated in the central
nervous system (CNS). In the hippocampus, TRPA1 is
linked with activation of the cannabinoid receptor CB1 upon
hippocampal formation [147]. It is also expressed in neurons
of the nucleus supraopticus. TRPA1, most likely together
Pflugers Arch - Eur J Physiol (2012) 464:425–458
with TRPV1, is involved in excitatory synaptic inputs to the
magnocellular neurosecretory cells (MNCs) that produce
vasopressin in the supraoptic nucleus (SON). TRPA1 exists
at presynaptic terminals to the MNCs and enhances gluta-
mate release in the SON [312].
In the brain stem, TRPA1 is expressed on visceral affer-
ent pathway and regulates glutamate release. The TRPA1
agonists, such as allylisothiocyanate (AITC), effect mechan-
ically dispersed nucleus tractus solitarii neurons (~60 %
neurons), suggesting non-nociceptive responses related to
TRPA1 [262].
In astrocytes, which contribute to the formation and function
of synapses, TRPA1 expression might be linked with regula-
tion of inhibitory synapses. TRPA1 activation evokes frequent
and highly localized ‘spotty’ Ca2+ membrane-near microdo-
mains. The reduction of astrocyte resting Ca2+ concentrations
mediated by TRPA1 channels decreases the interneuron inhib-
itory synapse efficacy by impaired GABA transport, resulting
in elevated extracellular GABA contents [252].
Inner ear
The unique ARD structure of TRPA1 hinted that it might
possibly be a mechanosensitive channel in the inner ear
[60]. TRPA1 is expressed in the the stria vascularis, the
organ of Corti and outer and inner hair cells (OHCs and
IHCs) of the cochlea [258, 272].
Cardiovascular system
In vascular endothelial cells, TRPA1 function is related to
endothelium-derived hyperpolarizing factor (EDHF)
responses [80, 263]. TRPA1 is activated by environmental
irritants, pungent compounds found in foods such as garlic,
mustard, and cinnamon, as well as metabolites produced dur-
ing oxidative stress. TRPA1 agonists cause arterial dilation
through two distinctive pathways. TRPA1 channels expressed
on perivascular nerves mediate vasodilatation of peripheral
and cerebral arteries in response to chemical agonists through
release of CGRP. In the endothelium, TRPA1 is mainly con-
centrated within myoendothelial junction sites. Its activation
causes endothelium-dependent smooth muscle cell hyperpo-
larization and vasodilatation that requires the activity of small
and intermediate conductance Ca2+ -activated K+ channels
[79, 233].
Expression of TRPA1 in the pancreas
TRPA1 is abundantly expressed in rat pancreatic islets [45].
Allylisothiocyanate and 15-deoxy-Delta [12, 14]-prostaglandin
J2 (15dPGJ2), significantly induced Ca2+ influx in β cells, and
the specific TRPA1 inhibitors block the effects elicited by
electrophilic activation [213].
Pflugers Arch - Eur J Physiol (2012) 464:425–458
Gastrointestinal tract
In the small intestinal and colonic mucosa, TRPA1 functions
together with intestinal odorant receptors (ORs). As the gut
lumen is continually exposed to a great variety of agents,
including noxious compounds, TRPA1 acts as a chemosensor
that detects the luminal environment and modulates gastro-
intestinal functions. Stimulation of ORs modulates epithelial
permeability and electrogenic anion secretion in human and
rat colon which is most likely mediated by activation of
TRPA1 channels [130]. A relatively high expression of
TRPA1 is also observed in enterochromaffin cells throughout
the GI tract. It has been shown that TRPA1 agonists
delay in vivo gastric emptying through serotonergic path-
ways [73].
Respiratory system
TRPA1 is highly expressed in most nonneuronal cell types
forming the pulmonary system where it plays a fundamental
role not in normal airway function but becomes extremely
important for acquired diseases [1, 44]. It has been shown
that activation of TRPA1 might modulate the chemokine
release in inflamed airways [196].
Skin
In nonneuronal skin cells, such as human keratinocytes and
fibroblasts, activation of TRPA1 mediates secretion pattern
of the eicosanoids, such as prostaglandin E2 PGE2 and
leukotriene B4 (LTB4) and provokes a long-lasting local
erythema [127]. In the basal layer of the epidermis, TRPA1
is also co-localized with the melanocyte marker, pMel-17. It
has been demonstrated that in melanocytes TRPA1 affects
the expression of proinflammatory cytokines, including
interleukin-1α and β (IL-1α, IL-β) [12].
Dental pulp
In human teeth, TRPA1 is highly expressed in dental pulp
fibroblasts where it might be involved in cold responses and
pain associated with mechanotransduction [83]. The major-
ity of pulpal afferents also express TRPA1, and therefore
TRPA1 might be considered an important target for the
treatment of dental sensitivity [43, 116, 141].
Stem cells
Neural crest-like stem cells from neonatal mouse epidermis
can be converted to Schwann precursor cells, pigmented
melanocytes, chondrocytes, or functional sensory neurons
showing voltage-gated sodium channels and TRPA1
[266].
429
Cellular distribution and turnover of TRPA1
TRPA1-mediated nocifensive behavior can be sensitized in
vivo via protein kinase A (PKA)/phospholipase C (PLC)
signaling and/or application of TRPA1 agonists such as
mustard oil (MO). Since both stimuli increase TRPA1
expression in the plasma membrane and application of MO
enlarges cell capacitance, one possible mechanism might be
linked with increased exocytosis in these cells. In line with
this hypothesis, tetanus toxin attenuates the response to the
second of two pulses of MO in neurons, suggesting that
vesicle fusion increases functional TRPA1 expression at the
plasma membrane. Thus, translocation of TRPA1 to the
plasma membrane might represent one of the mechanisms
controlling TRPA1 functionality upon acute activation or
inflammatory signals [248].
The cellular levels of TRPA1 seem to be controlled by a
potential post-translational mechanism related to the human
tumor suppressor CYLD. CYLD is an ubiquitin hydrolase
that binds to TRPA1 and de-ubiquinates the channel. De-
ubiquitination causes increased cellular levels of TRPA1 pro-
teins. Thus, oncogenic mutations of CYLD might alter
TRPA1-mediated responses by rendering the channel suscep-
tible to ubiquitinylation [259]. Thus, association of TRPA1
with enzymes of the ubiquitin pathway might be important
mechanisms that regulate cellular levels of TRPA1.
Biophysical properties of TRPA1
The pore and single channel properties
The constitutive open TRPA1 channel evokes outwardly
rectifying currents (Aa, C) that rapidly inactivate at positive
potentials (Bb,c). The nature of this inactivation is still
unknown. The activation of TRPA1 by electrophilic com-
pounds results in large inward currents whereas the outward
rectification is mostly abolished (Bb). In contrast, TRPA1
activation with non-electrophilic compounds still displays
outward rectification. The reason for these differences still
has to be elucidated. Extracellular Ca2+ ([Ca2+]e) level has
an effect on TRPA1 currents. In the presence of [Ca2+]e
activated TRPA1 currents decline rapidly (decay, desensiti-
zation C) whereas in its absence, both current activation as
well as current decay, are delayed (Fig. 3).
As for other TRP channels, the pore of TRPA1 is formed
by the selectivity filter and the pore helix of the four subunits
in the tetrameric channel. Based on the relative permeability
of the nonstimulated channel to cations of different size, the
TRPA1 pore has a diameter of approximately 11 Å. It is also
predicted that binding of Ca2+ in the pore may hinder mono-
valent cation permeation, resulting in a large fractional Ca2+
current. Approximately 17 % of the inward TRPA1 current is
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Fig. 3 Whole cell and single channel currents of mouse TRPA1
expressed in HEK293 cells. a Whole cell current before and after
application of 50 mM MO. Note that a fraction of the current is already
constitutively activated. The current–voltage relations are shown below
the time course of MO activation (red MO). Note the inactivation at
positive potentials. Holding potential is 0 mV. In the extracellular
solution 1.5 mM CaCl2 are present. b TRPA1 currents obtained from
voltage steps (−150 to +100 mV). Note the deactivation at negative
carried by Ca2+. This surprisingly high fractional Ca2+ current
places TRPA1 as the third most Ca2+ permeable TRP channel
(after TRPV5 and TRPV6).
The residue Asp918 seems to play a decisive role in
determining the Ca2+ permeation through this channel
[136, 211]. Another residue, Glu923, likely located in the
outer pore turret, seems to create a Ca2+ microdomain at the
pore entry [33]. Since TRPA1 seems to be partially a con-
stitutive open channel, sustained and increased levels of
endogenous TRPA1 agonists might be present especially
in various pathophysiological conditions [149].
In outside-out patch recordings, using N-methyl-D-
glutamine (NMDG+) as the sole external cation and Na+ as
the internal cation, TRPA1 activation results in dynamic
Pflugers Arch - Eur J Physiol (2012) 464:425–458
potentials and in slow activation at positive potentials. TRPA1 is a
voltage-dependent channel. c In divalent free solutions single channel
conductance of TRPA1 is ~115 pS. Voltage ramps were applied from -
100 to +100 mV, cell attached patch, constitutively open channel. d In
the presence of extracellular Ca2+, TRPA1 shows a fast activation and
is inactivated during application of MO. e Both, MO-mediated activa-
tion and inactivation of TRPA1 are delayed in the absence of extrac-
ellular Ca2+ (Nilius, Prenen unpublished)
changes in permeability to NMDG+ [52, 295]. This is due to
a progressive but reversible pore dilation process that also
causes an increase in divalent cation selectivity and fractional
Ca2+ current [19]. Mutations of the critical pore residue Asp918
reduces the divalent permeability and fractional Ca2+ current
but also prevents MO-induced increases in Ca2+ permeation
[136]. Obviously, TRPA1 can exist in at least two distinct open
states: a restricted and a dilated state. The restricted state is a
non-selective cation channel, whereas the dilated state allows
influx of much larger molecules, e.g. Yo-Pro (Mw ~630) and
NMDG. It is under discussion whether the dilated state is
regulated by extracellular calcium. Amiloride and its analogue
5-(N,N-Dimethyl)amiloride (DMA) block the channels but in
the dilated state these open channel blockers penetrate deeper
Pflugers Arch - Eur J Physiol (2012) 464:425–458
into the pore providing a more efficient block [18]. It is very
likely that the pore region is involved in channel gating. Res-
idues within the S6 inner pore-forming region of human
TRPA1 contribute to gating by electrophiles in a voltage-
dependent manner. The alanine substitution in the conserved
mid-S6 Pro949 (Pro949Ala) strongly affects the activation/
deactivation and ion permeation. The proline 949 is structurally
required for the normal functioning of the TRPA1 channel.
Another mutation, Asn954Ala, generates a constitutively open
channel, suggesting a role in stabilizing the closed conforma-
tion. Alanine substitutions in the distal GlyXXXGly-motif
decrease the relative permeability of the channel for Ca2+ and
strongly affected its activation/deactivation properties, indicat-
ing that the distal Gly 962 stabilizes the open conformation.
The glycine 958, on the other hand, provides additional tuning
leading to decreased channel activity. The inner pore region
probably controls conformational changes required for transi-
tions between open and closed states of the TRPA1 channel
[27].
In contrast to TRPA1 pore properties that change with
different activation modes, single channel properties depend
on the experimental condition. In divalent cation-free solution,
TRPA1 has a single channel conductance of ~112 pS at
negative and positive potentials. In the presence of extracel-
lular Ca2+ and Mg2+, the conductance at negative potentials
(inward direction) is reduced to 55–65 pS, depending on the
concentration of the divalent cations. TRPA1 has a rather high
Ca2+ selectivity, PCa/PNa is ~6 for the constitutive open chan-
nel and ~9 for the channel activated with electrophilic agonist.
The fractional Ca2+ currents are respectively ~17 % for the
constitutively open and 23 % for the agonist activated channel
[136]. The magnesium ion blocks the open channel but is still
permeable at negative potentials (PMg/PNa ~2, PBa/PNa ~3.5).
Relative inorganic cation permeabilities are Li+ >Na+ >K+ 0
Rb+ >Cs+ (1.2 : 1 : 0.98 : 0.98 : 0.95), indicating a strong field
strength binding cation site in the channel (Eisenman XI).
Organic cations permeate with the sequence of Na+ ~Dime-
thylamine >Trimethylamine >Tetramethylammonium
>NMDG+ (1 : 0.99 : 0.7 : 0.4 . 0.1). Electrophilic activators
increase the permeability to large organic cations due to a pore
dilation of ~1 to 3 Å [33, 136].
Single channel properties of TRPA1 seem to be also
regulated by co-expression with TRPV1. Very likely,
TRPA1 and TRPV1 proteins form a complex that can
influence single-channel currents through TRPA1. Co-
expression of TRPV1 with TRPA1 results in outward
rectification of single-channel current–voltage relation-
ships (I-V) and substantial modulation of the open prob-
ability at negative holding potentials. TRPV1 does not
influence the single channel conductance in [Ca2+]e-free
solution. Thus, single-channel properties of TRPA1 are
regulated by TRPV1 independently of intracellular Ca2+
but rather by direct interaction [257].
431
Structure—function relationship in channel gating
TRPA1 is regulated by negatively charged ligands such as
phosphoinositides or inorganic polyphosphates, most likely
through an interaction with as yet unidentified positively
charged domain(s) in the cypoplasmic tails. The positively
charged residues in the C-terminal tail of TRPA1, Lys969,
Arg975, Lys988 and Lys989, are involved in electrophilic
agonist and voltage-dependent gatings. Another positively
charged region is centered around Lys1048 and Lys1052.
Single alanine mutations in this region completely abolished
agonist and voltage-dependent activation. In the distal por-
tion of the C-terminus, the alanine substitutions at Lys1092
and Arg1099 reduce the channel sensitivity to electrophilic
agonists, and increased the voltage-induced steady-state
responses. Thus, a stretch of basic residues in the C terminus
represent possible interaction sites for negatively charged
molecules that are generally considered to modulate TRPA1
[244].
Modulation and regulation of TRPA1
TRPA1 is considered as a very attractive target for develop-
ment of analgesic and anti-inflammatory drugs. Therefore,
the pharmacology of the TRPA1 channel is of huge impor-
tance. Unfortunately, striking differences between human
and rodent TRPA1 homologues complicate TRPA1-
targeted drug discovery. Many compounds that show antag-
onistic effect with human TRPA1 can behave as agonists or
show no activity when examined in rat and mouse. Thus,
functional differences have to be taken carefully into
account when the modulation of this channel is considered
(see also [31].
Electrophilic activators
TRPA1 has a remarkable gating promiscuity. Electrophilic
TRPA1 ligands of environmental-, dietary- or endogenous
origin modify nucleophilic cysteine and lysine residue(s) in
the N-terminus of the channel [15]. Chemical activators of
TRPA1 are structurally as diverse as their source: isothio-
cyanates (the pungent compounds in MO, wasabi, and
horseradish) [14, 129], methyl salicylate (in winter green
oil) [14], cinnamaldehyde (in cinnamon) [14] allicin and
diallyl disulphide (in garlic) [23, 174], acrolein (an irritant
in vehicle exhaust fumes and tear gas) [23] and Δ9 tetra-
hydrocannabinol (Δ9THC, the psychoactive compound in
marijuana [129, 219, 260].
Allyl isothiocyanate from MO is one of the most efficient
electrophilic activators of TRPA1. In human TRPA1, sulf-
hydryl reacting agents modify cysteines Cys619, Cys639
and Cys663 located between the last ARD and S1 [119].
432
In the mouse TRPA1 homologue the most reactive cysteine
residues are Cys415 and Cys422 between 10th and 11th
ARDs and, similarly to the human version, Cys622 between
last AR and S1 [173] (for a review see [47]) (for a review
see [225]). Other electrophiles, such as cinnanaldehyde
(CA), super CA (SC), SC –alkyne (SCA), acrolein, 2-
pentenal, MO, alkyne (MOA), iodoacetamide (IA), IA-
alkyne (IAA), and 2-(trimethylammonium)ethyl methane-
thiosulfonate bromide (MTSEA; used for cysteine scan-
ning), are capable of reacting with cysteine residues and
act as TRPA1 activators. Although it is now generally
accepted that TRPA1 is activated through covalent modifi-
cation of specific cysteines, the precise mechanism and the
chemistry of this covalent modification with unsaturated
carbonyl-containing compounds is unclear. Channel activa-
tion occurs with chemicals that react with cysteine residues
via alkylative conjugate addition [241], but unravelling of
the molecular details underlying activation and deactivation
of TRPA1 via covalent modifications still remains an excit-
ing challenge.
Importantly, TRPA1 is a sensor for oxygen. O2 sensing is
based upon disparate processes. Prolyl hydroxylases
(PHDs) exert oxygen-dependent inhibition on TRPA1 activ-
ity in normoxia. However, a direct O2 action overrides the
inhibition via the high sensitivity of TRPA1 to cysteine-
mediated oxidation in hyperoxia. Therefore, TRPA1 is acti-
vated through relief from the PHD-mediated inhibition in
hypoxia. TRPA1 in the vagal and sensory neurons is there-
fore a critical sensor of both hyperoxia and hypoxia which
will both enhance vagal discharges. TRPA1 is thus an excit-
ing new player in O2-sensing [269]. In addition, the hypoxia
inducible factor-1α (HIF1α) is also coupled with the
expression of TRPA1 [113].
In general, reactive oxygen species (ROS) that cause
cysteine oxidation or disulfide formation, reactive nitrogen
species (RNS) like nitric oxide (NO) that mediate S-
nitrosylation, and reactive carbonyl species (RCS), like
electrophilic prostaglandins (PG) and α/β unsaturated alde-
hydes that alkylatively modify cysteine, are all potential
TRPA1 activators [270, 271, 280].
It is widely known that inhalation of ozone is a major health
risk in industrialized nations, impairing lung function through
sensory neural-mediated pathways (vagal nociceptive C type
bronchopulmonary nerves). Ozone can stimulate TRPA1 but
has no effect on TRPV1 [278]. Hydrogen peroxide (H2O2), a
common industrial and household chemical, is also generated
within cells, causing pain sensation via activation of TRPA1.
Effects of H2O2 can be mimicked by other ROS as well as by
RNS. Cysteine-reducing agents, such as dithiothreitol (DTT),
suppress H2O2-induced TRPA1 activation, whereas cysteine-
oxidizing agents activated TRPA1 [247]. Oxygen (O2) is a
prerequisite for cellular respiration in aerobic organisms but
also elicits toxicity. TRPA1 senses O2 in mechanistically
Pflugers Arch - Eur J Physiol (2012) 464:425–458
distinct ways: prolyl hydroxylases (PHDs) exert O2-depend-
ent inhibition on TRPA1 but direct O2 action of TRPA1 can
override this inhibition, and, in hypoxia TRPA1 is activated
through relief from the PHD-mediated inhibition [269].
TRPA1 confers a sensitivity towards near ultraviolet
(UVA) light. UVA light activates TRPA1 currents in a
wavelength-dependent and membrane-delimited manner.
Light-induced TRPA1 activation is caused by highly ROSs
and provides an additional mode of activation, which ren-
ders TRPA1 a likely molecular candidate in processes lead-
ing to painful or burning sensations during photodynamic
therapy or upon local application of hydrogen peroxide
[118].
Among RNS, NO is a most potent TRPA1 activator. It
can induce acute pain in humans and plays an important role
in pain sensitization caused by inflammation and injury in
animal models. NO acts both in the central nervous system
via a cyclic GMP pathway and in the periphery on sensory
neurons through direct activation of TRPA1 (and also
TRPV1). The endothelial tetrahydrobiopterin (BH4), an
essential co-factor for NO production, causes activation of
a subset of DRG neurons by TRPA1 activation [191]. Nitro-
oleic acid (9-OA-NO2), an electrophilic fatty acid byprod-
uct of NO and nitrite reactions is also a potent TRPA1
activator. Excessive nitric oxide during inflammation (nitra-
tive stress), leads to the nitration of phospholipids resulting
in the formation of this highly reactive cysteine modifying
agent. 9-OA-NO2 failed to activate TRPA1 in which the
cysteines at position 619, 639 and 663 and the lysine at 708
had been mutated (the TRPA1-3C/K-Q mutant) [274]. The
effects of OA-NO2 are blocked by DTT but could not be
prevented or reversed by an NO-scavenger carboxy-PTIO
[250].
Another important RNS, hydrogen sulfide (H2S) is a mal-
odorous gas that functions as an endogenous gasotransmitter
in humans and is involved in a wide variety of processes
including nociceptive processes [192]. H2S evokes CGRP
release from sensory neurons of isolated rat tracheae, increas-
ing microcirculation in several organs, and TRPA1 receptor
activation might be a major mechanism underlying the vaso-
active effects of H2S [231]. Neurogenic inflammation, hyper-
algesia and pain caused by H2S are all enhanced under acidic
conditions [214]. Hydrogen sulfide increases cAMP levels in
neuronal and glial cell lines and primary neuron cultures.
Hydrogen sulfide-induced [Ca2+]i responses are inhibited by
the reducing agent DTT. [214]. Beside effects on TRPA1, H2S
may be involved in multiple signaling pathways and produce
various effects on ion channels such as T-type calcium chan-
nels and ATP-sensitive K+ (KATP) channels, which may inhibit
or promote nociception. T-type Ca2+ channel blockers
together with TRPA1 channel blockers efficiently attenuate
NaHS/H2S-induced mechanical hyperalgesia and allodynia in
rodents [215].
Pflugers Arch - Eur J Physiol (2012) 464:425–458
High concentrations of carbon dioxide (CO2), as found in
carbonated beverages, evoke a mixture of sensations,
including a stinging or pungent quality. The stinging sensa-
tion originates from activation of TG nociceptors that
express TRPA1 and innervate the respiratory, nasal, and oral
epithelia. Carbon dioxide diffuses into cells and produce
intracellular acidification thereby gating TRPA1. Consistent
with this mechanism, TRPA1 is activated in a dose-
dependent manner by intracellular protons [288]. Acetic
acid produces an irritating sensation that can be attributed
to activation of TRPA1 nociceptors. Other weak organic
acids, including propionic, formic, and lactic acid, but not
strong acids, also activate TRPA1. Importantly, preactiva-
tion by reactive electrophiles sensitized TRPA1 channels to
weak acids [99, 287]. Alkaline pH also causes pain via
activation of TRPA1. Two N-terminal residues, Cys422
and Cys622, are responsoble for high pH perception. Pain
behaviors evoked by intraplantar injection of ammonium
chloride are completely reduced in TRPA1 ko mice [96].
Cyclopentenone PGs, 15dPGJ2, PGA2, and PGA1,
formed by dehydration of their respective parent PGs,
PGD2, PGE2, and PGE1, possess a highly reactive α, β -
unsaturated carbonyl group and can gate TRPA1. Thus,
15dPGJ2 activates TRPA1 expressed in HEK cells as well
as in mouse TG neurons [61]. This effect was not mimicked
by their non-electrophilic precursors, PGE2, an aldol, PGD2,
a saturated cyclopentanone, or PGB2 a β, β-disubstituted
enone, where the electrophilic element is lacking or is not
reactive due to steric hindrance. Cyclopentenone PGs produce
pain by direct stimulation of nociceptors via TRPA1 activa-
tion, and are proalgesic. Thus, preventing TRPA1-dependent
nociceptor activation by cyclopentenone PGs with TRPA1
antagonism may suppress pain without the adverse effects of
cyclooxygenase inhibitors [184], that act upstream and less
selectively in the PG cascade, by inhibiting cyclooxygenases.
Tissue damage release factors, such 4-hydroxynonenal
(4-HNE) and another endogenously-produced alkenal,
4-oxononenal, are potent TRPA1 activators [276].
4-Hydroxynonenal is an α,β-unsaturated hydroxyalkenal
which is produced in inflammed tissues during peroxidation
of membrane phospholipids by ROS. It evokes release of
substance P and CGRP from nerve endings, causing extrav-
asations of plasma proteins into the surrounding tissue. The
activation of TRPA1 with 4-HNE promotes acute pain,
neuropeptide release and neurogenic inflammation.
4-Hydroxynonenal acts via covalent modification of the
cysteine/lysine residues in the TRPA1 NH2-terminus since
the TRPA1-3C/K-Q mutant is insensitive to 4-HNE [281].
Effects of endogenous 4-HNE are abolished with DTT,
suggesting that they are mediated by a redox process. In
contrast, the action of the alkenyl aldehydes and 15d-PGJ2
is not reversed by DTT, suggesting that these agents form
irreversible Michael adducts [3].
433
Apart from naturally occurring chemical activators,
TRPA1 is also sensitive to a host of compounds used in
every aspect of modern life, including military use. Constit-
uents of tear gases such as methyl isocyanate, 1 H-dibenz[b,
e]azepines (morphanthridines) and dibenz[b,f][1,4]oxaze-
pines, mediate TRPA1 activation [104]. The release of
methyl isocyanate in Bhopal, India, caused the worst indus-
trial accident in history [29]. Toluene diisocyanate (TDI) is
used as a chemical intermediate in the production of polyur-
ethane polymers such as foams, coatings, and elastomers. It
is a reactive hazardous irritant, causing respiratory symp-
toms such as cough, rhinitis, dyspnea and chest tightness in
exposed workers [275]. Formaldehyde and its water solu-
tion, formalin, directly activate TRPA1 and are widely used
in animal models for testing analgesic compounds [188].
Painful responses to iodoacetamide, a nonspecific cysteine-
alkylating agent, are due to TRPA1 activation [176]. TRPA1
is also activated by disulfiram (Antabuse), a compound used
in the treatment of alcohol abuse, and by the anti-fungal
agent, chlordantoin [177].
Non-electrophilic modulators
Beside the huge number of electrophilic activators, TRPA1
can also be modulated by other compounds that are unlikely
to induce covalent modifications of the channel proteins.
In general, anesthetic agents can induce a paradoxical
activation and sensitization of TRPA1. Propofol (2,6-
diisopropylphenol), a commonly used intravenous anes-
thetic, elicits intense pain upon injection. TRPA1 is a key
molecule for propofol-induced excitation of sensory neu-
rons [92]. Propofol’s effects on sensory neurons may be
clinically important and may contribute to peripheral sensi-
tization to nociceptive stimuli in traumatized tissue [320].
In the same line, general anesthetics (GAs), which
depress the CNS, can also activate peripheral nociceptive
neurons. The pronociceptive effects of GAs combined with
surgical tissue damage could even lead to a paradoxical
increase in postoperative pain and inflammation [185]. Clin-
ical concentrations of noxious intra-venal and inhalation
GAs excite sensory neurons by selectively activating
TRPA1. Isoflurane and desflurane are pungent, while sevo-
flurane and halothane are not, and TRPA1-dependent neuro-
genic inflammation is more severe in mice anesthetized with
pungent- compared with nonpungent anesthetics.
A further surprise came with the identification of local
anesthetics (LAs) as activators of the irritant receptor TRPA1.
Lidocaine, inhibits cellular excitability by blocking voltage-
gated Na + channels, but can activate TRPA1 in a
concentration-dependent manner. This activation is blocked
by the TRPA1-antagonist HC-030031. Interestingly, lidocaine
can also act as an inhibitor of TRPA1, an effect more evident
with rodent than human TRPA1. This species-specific
434
difference is probably linked to the pore region (S5 and S6)
[167]. Local anesthetics like lidocaine and procaine also medi-
ate glutamatergic spontaneous excitatory transmission in sub-
stantia gelatinosa (SG) neurons. Lidocaine dose-dependently
and reversibly increases the frequency but not the amplitude of
spontaneous EPSCs in SG neurons. This presynaptic enhance-
ment is due to activation of TRPA1 in nerve terminals presy-
naptic to SG neurons that increase the spontaneous release of L-
glutamate [227].
Fenamate nonsteroidal anti-inflammatory drugs (NSAIDs)
can also activate and sensitize TRPA1. Several nonelectro-
philic NSAIDs, including flufenamic, niflumic, and mefe-
namic acid, as well as flurbiprofen, ketoprofen, diclofenac,
and indomethacin, reversibly activate TRPA1. The response
to fenamate agonists is blocked by TRPA1 antagonists. Fena-
mate NSAIDs also potentiate the activation of TRPA1 by
electrophilic compounds [122].
Non-electrophilic compounds can also be metabolized to
electrophilic products that can affect TRPA1 function.
N-Acetyl-p-aminophenol (paracetamol, acetaminophen,
APAP) is the most common antipyretic/analgesic medicine
worldwide. In case of APAP overdose, its metabolite,
N-acetyl-p-benzoquinoneimine (NAPQI), leads to important
liver damage. NAPQI, like other TRPA1 activators, is an
electrophilic molecule and stimulates TRPA1, causing air-
way neurogenic inflammation. This inflammatory responses
evoked by NAPQI and APAP can be abolished by TRPA1
antagonists [204].
Very often compounds used in therapeutics and cosmetics
are potent TRPA1 activators. Parabens, alkyl esters of
p-hydroxybenzoate often added to pharmaceuticals, cosmetics
and food products as antibacterial agents can behave as
TRPA1 activators [95]. Calcium antagonists such as 4 differ-
ent 1,4-dihydropyridines (nifedipine, nimodipine, nicardipine
and nitrendipine) and the structurally related L-type calcium
channel agonist BayK8644, exert powerful activating effects
on TRPA1. Activation by nifedipine is reduced by camphor
and the selective TRPA1 antagonist HC03001 [90]. Similarly,
5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), a classic
Cl- channel blocker, potently activates human TRPA1. The
action of NPPB suggests a possible close interaction between
S5 and the N-terminal domains of the channel. As indicated by
the analysis of NPPB derivatives, NPPB activates TRPA1
through a structure-specific mechanism [171].
Primary alcohols cause skin, eye or nasal irritation via
activation of TRPA1. Higher alcohols such as 1-butanol,
1-hexanol and higher, activate TRPA1 proportional to the
carbon chain length, i.e. the potency increased with the
carbon chain length. Interestingly, activation by primary
alcohols also requires Cys665 as well as His983 residues
in the N-terminal part of TRPA1 [151].
In general, TRPA1 is a non-covalent sensor of polyunsa-
turated fatty acids (PUFAs), which contain at least 18
Pflugers Arch - Eur J Physiol (2012) 464:425–458
carbon atoms and three unsaturated bonds, Those PUFAs
activate TRPA1 to excite primary sensory neurons and enter-
oendocrine cells. They act non-covalently and independently
of known ligand binding domains located in the N-
terminus [195].
Many non-covalent modulators of TRPA1 function in a
bimodal fashion, i.e. they activate the channel at low con-
centration, and inhibit it at higher concentrations. Menthol
from Mentha piperita, a known TRPM8 activator, is also a
bimodal modulator of TRPA1. Low-micromolar concentra-
tions of menthol cause channel activation, whereas higher
concentrations lead to a reversible channel inactivation
[134]. This is only true for human TRPA1 whereas its non-
mammalian versions are insensitive to menthol. Mouse-
human TRPA1 chimeras reveal that the pore region between
S5 and S6 is the critical domain determining whether men-
thol can act as an inhibitor. Specific residues, Thr877,
Ser876 and Gly878 are critical for menthol responsiveness
but determine also the function of other nonreactive TRPA1
modulators, such as binding of the blocker AMG 5445 and
AP18 [305]. Similarly to menthol, the super-cooling agent
icilin (AG-3-5) activates not only TRPM8 as but also
TRPA1. Icilin can induce a rapid, long-lasting and dose-
related hyperthermia in rats. Pretreatment with NOS inhibtor
N(G)-nitro-l-arginine methyl ester hydrochloride (l-NAME)
attenuated this hyperthermia. TRPM8/TRPA1 activation
induced hyperthermia requires both NO production and N-
methyl-D-aspartate (NMDA) receptor activation [70].
Another example of species-dependent activator of
TRPA1 is caffeine. Caffeine from Coffea arabica, activates
mouse TRPA1 but suppresses its human version. The region
between residues Thr231 and Asp287 in the distal N-terminal
cytoplasmic region of mouse TRPA1 is critical. The mutation
of mouse TRPA1, Met268Pro, changes the effect of caffeine
from activation to suppression [198, 199]. Similarly, nicotine
from Nicotinia tabacum or its analogue, anabasin from Nic-
otiana glauca, are bimodal TRPA1 modulators. Topical appli-
cation of nicotine, as used in nicotine replacement therapies,
causes irritation of the mucosa and skin due to TRPA1 acti-
vation. In contrast, higher concentrations inhibit the channel.
It is thought that blocking of TRPA1 activation may facilitate
the development of smoking cessation therapies with less
adverse effects [273].
The gating promiscuity of TRPA1 is also illustrated by the
effects of several metals. Zinc, an essential biological trace
element, is required for the structure or function of over 300
proteins. High concentrations of zinc have cytotoxic effects and
can cause pain and inflammation. Surprisingly, zinc activates
TRPA1 through a unique mechanism that requires zinc influx
through TRPA1 channels and subsequent activation via specific
intracellular cysteine and histidine residues. TRPA1 is highly
sensitive to intracellular zinc, as low nanomolar concentrations
activate TRPA1 and modulate its sensitivity [121]. The
Pflugers Arch - Eur J Physiol (2012) 464:425–458
antifungal and amoebicidal drug clioquinol (CQ) was with-
drawn from the market when it was linked to an epidemic of
subacute myelo-optico-neuropathy (SMON). Clioquinol exerts
its anti-parasitic actions by acting as a Cu/Zn chelator and
ionophore. Local injections of CQ produce mechanical hyper-
algesia and cold hypersensitivity through activation of TRPA in
a Zn2+-dependent manner. Direct application of Zn2+ to the
intracellular face of excised, inside-out patches activates
TRPA1. Thus, TRPA1 acts a sensor of intracellular Zn2+, and
Zn2+ ionophores, such as CQ, activate TRPA1 by increasing
intracellular Zn2+ concentrations [4]. Similarly to zinc, two
other heavy metals, cadmium and copper also directly activate
TRPA1, resulting in stimulation of pulmonary sensory neurons
[110].
In the light of the increasing use of non-pungent capsi-
noids as slimming agents to enhance energy metabolism by
activating sympathetic nervous, it is interesting to highlight
that TRPA1 is also activated by these compounds, e.g.
capsiate. Capsinoids activate TRPA1 by an as yet unknown
mechanism, which does not involve covalent modifications
of reactive Cys or Lys residues [253]. Capsinoids are unsta-
ble compounds that quickly generate electrophilic quinone
methides, and this mechanism, somewhat similar to that
involved in the activation by the metabolites of APAP, might
underlie their action on TRPA1 [172].
Last but not least, TRPA1 is also activated by Δ9THC,
the psychoactive compound in marijuana [129, 219, 260].
Also two non-psychoactive cannabinoids, cannabidiol
(CBD) and cannabichromene (CBC), are known to modu-
late TRPA1. Specific agonists of TRPA1 channels and syn-
thetic inhibitors of endocannabinoid cellular reuptake exert
effects similar to those of CBC and CBD, stimulating
descending pathways of anti-nociception and caused anal-
gesia by interacting with several target proteins involved in
nociceptive control [64, 179]. THC-induced CGRP release
and vasorelaxant responses to sensory nerve stimulation
also proceed via TRPA1 activation [301]. Morphine and
its derivatives and analogues are key drugs in pain control
but are proalgesic at high concentrations, and short-lasting
painful sensations are known upon dermal application of
morphine. Just like cannabinoids, morphine as well as
naloxone induce release of CGRP via activation of TRPA1
[93]. Interestingly, TRPA1 is also activated by CB antago-
nists, e.g. AM251 and AM630, representing an alternative
target for these drugs [222]. Six phytocannabinoids [CBD,
THC, CBD-acid, THC-acid, cannabichromene (CBC) and
cannabigerol (CBG)] showed potent TRPA1 activating
properties. None of these compounds could activate TRPM8
but, with the exception of CBC, they could all antagonize
TRPA1 activation by menthol or icilin. The unusual canna-
binoid sesqui-CBG, isolated from the waxy fraction of a
variety of fiber hemp (Cannabis sativa) could inhibit
TRPA1 responses more potently than its lower prenilogue
435
CBG [228], suggesting that, by proper chemical manipula-
tion, the TRPA1 activating and inhibiting properties of
cannabinoids could be dissected. Clearly, phytocannabi-
noids and cannabis extracts exert some of their pharmaco-
logical actions by interacting with TRPA1 and possibly
TRPM8 channels, with potential implications for the treat-
ment of pain and cancer [65].
TRPA1 antagonism
The huge importance of TRPA1 in pain, inflammation and
many other potential indications in acquired diseases has
initiated an increasing demand for specific antagonists. The
first TRPA1 antagonists were reported in 2007,and were based
on a xanthine structure, as exemplified by HC-030031 (Hydra
company), still the most widely used product. More recently,
phtalimide derivaties (e.g. the high nano-molar ligand
Glenmark 17, 34) and imidazo-uridine derivatives (e.g.
Glenmark 8, 39) were disclosed by the Glenmark company.
All these inhibitors are non-electrophilic, and presumably act
via non-covalent interaction. Interestingly, also camphor, a
monoterpene derived from Cinnamomum camphora, acts as
a natural TRPA1 antagonist [8, 16, 236, 246].
Among electrophilic compounds, several oximes have
been recently disclosed as antagonists of TRPA1. Oximes
related to AP18 possess both agonist and antagonist activity
[66]. Another oxime-derived compound, A-967079, is a
potent nano-molar blocker of human TRPA1 that attenuates
cold allodynia produced by nerve injury but does not alter
noxious cold sensation and does not alter body temperature
[51]. Other electrophilic agonist with a nano-molar range of
action are Abbott A, Renovis 11, Amgen AMG 7160, 2504,
9090, 5445, and the Abbott CMP1, 2, 3 [236]. Recently, a
new series of 7-substituted-1,3-dimethyl-1,5-dihydro-
pyrrolo[3,2-d]-pyrimidine-2,4-dione derivatives have been
developed as efficient TRPA1 antagonists [21].
Interestingly, heat suppresses the activation of TRPA1.
Thus, agonist-induced TRPA1 currents in HEK293 cells are
suppressed by warm temperatures, and almost abolished at
39 °C. This inhibition occurs when TRPA1 is activated by
both electrophilic and non-electrophilic agonists. Warming
also attenuates TRPA1 mediated ionic currents in sensory
neurons, which may explain, the well-know effect of
warmth to attenuate pain [293].
Activation by cold
TRPA1 has been initially described as a cold-activated
channel [14, 260], but this view has now been questioned
([46, 129], for a critical review see [163]). TRPA1-expressing
primary afferents mediate noxious cold responses in anaes-
thetised rats, but the TRPA1 agonist cinnamaldehyde applied
to the skin in anaesthetised rats did not sensitize noxious cold-
436
evoked hind limb withdrawal. However, TRPA1 agonist sen-
sitized the noxious reflex withdrawal to heat, but not cold.
Block of the TRPA1 did not inhibit cold evoked activity in
either cinnamaldehyde sensitive or insensitive cold responsive
nociceptors. These results do not support the hypothesis that
TRPA1-expressing cutaneous afferents play an important role
in noxious cold responses [78].
However, recent papers have provided fairly convincing
evidence for direct activation of TRPA1 by cold, and have
identified a central role in pain for this most “sensitive”
sensory channel [159]. Thus, TRPA1 is activated by cold
in a Ca2+-independent and Ca2+ store-independent manner
[137, 246]. Cold plate and tail-flick experiments have also
revealed a TRPA1-dependent, cold-induced nociceptive
behavior in mice [68, 137], and it has been clearly demon-
strated that TRPA1-deficient mice display the loss of a
specific subset of cold-sensitive TG neurons. Similarly,
TRPA1 also contributes to cold-induced contractions in iso-
lated rat colon preparations [74]. Application of cold tem-
perature to these visceral afferents can evoke major
protective reflexes and thermoregulatory responses, and
TRPA1 is the major mediator of cold-evoked responses in
vagal visceral neurons. Most cold-evoked responses are
potentiated by TRPA1 agonists such as cinnamaldehyde,
menthol, and icilin, whereas camphor and HC03001 act as
blockers [89].
Mechano-activation
The mechanosensory role of TRPA1 and its contribution to
mechanical hypersensitivity in sensory neurons still remains
enigmatic. As an indication of mechanosensitivity, hyper-
tonic solution (HTS), but not hypotonic solutions, activates
TRPA1. Single-channel recordings show no difference in
conductances as compared with electrophilic activation. In
rat DRG neurons, HTS-evoked TRPA1 currents are blocked
by camphor. HTS depolarizes the membrane potential of
DGR neurons leading to the generation of action potentials
[319]. Another indication comes from the use of amphi-
pathic molecules such as trinitrophenol (TNP) and chlorpro-
mazine (CPZ). Trinitrophenol causes a membrane curvature
that leads to activation of TRPA1 [117]. In contrast, CPZ
blocks TRPA1 at positive potentials and activates at nega-
tive potentials [117].
Several evidences from in vivo experiments support a
role for TRPA1 as a mechanosensor. TRPA1 at sensory
afferent terminals in skin is required for their responsiveness
to both noxious chemical and mechanical stimuli. In skin-
nerve preparations, acute application of the selective TRPA1
antagonist HC-030031 inhibits all formalin responses in rat
C fibers. HC-030031 could also markedly reduce the
mechanically-evoked action potential firing in rat and wild
type mouse C fibers, particularly at high-intensity forces,
Pflugers Arch - Eur J Physiol (2012) 464:425–458
but has no effect on the mechanical responsiveness of Aδ
fiber nociceptors. In TRPA1-deficient mice, HC-030031 has
no effect on mechanically-evoked firing, indicating a
TRPA1-dependent mechanism [138]. TRPA1 is detected
not only on many thin-caliber axons and intraepidermal
endings, but also on many large-caliber axons as well as
lanceolate and Meissner endings. Epidermal and hair follicle
keratinocytes also express TRPA1. Thus, in nociceptor ter-
minals TRPA1 modulates mechanotransduction via a cell-
autonomous mechanism that very likely requires its modu-
latory role in keratinocytes that may interact with sensory
terminals to modify their mechanical firing properties [160].
Rapid focal mechanical stimulations evoke mechanically-
sensitive currents in DRG neurons. Small neurons (diameter
<27 μm) expressing TRPA1 give rise to C-fiber afferents in
vivo and show intermediately- (IAMC), rapidly- (RAMC) or
slowly-adapting (SAMC) mechanically-activated currents.
TRPA1 deletion in knockout mice significantly reduced max-
imum IAMC whereas other current types were unaltered in
small- and large-diameter neurons. The HC-030031 antago-
nist significantly decreased IAMC amplitudes in TRPA1 wild
type neurons. TRPA1 makes a specific contribution to normal
mechanosensation in a distinct subset of DRG neurons and
has the capacity to tune neuronal mechanosensitivity depend-
ing on its degree of activation or expression [35, 285].
TRPA1 might also function as a mechanosensor under
pathophysiological conditions. Inflammatory hypersensi-
tivity is characterized by behavioral reductions in with-
drawal thresholds to noxious stimuli. Skin primary
afferents have lowered thermal thresholds in inflamma-
tion, but whether these mechanical thresholds are altered
remains controversial. Interestingly, a subset of afferents
that is sensitized to mechanical stimulation by inflamma-
tion expresses TRPA1 [77]. Similarly, TRPA1 is impli-
cated in inflammatory pain in the gastrointestinal (GI)
tract. Sensory information from the GI tract is conducted
via different afferent fibers and different pathways.
Nodose ganglia and DRGs whose neurons innervate 3
different regions of the GI tract, all express TRPA1.
TRPA1 is required for normal mechano- and chemosen-
sory function in specific subsets of vagal, splanchnic and
pelvic afferents. Obviously, TRPA1 has mechanosensory
function and mediates nociception within the viscera in
normal and inflamed tissue [36]. Very likely TRPA1
alone is unable to mediate responses to mechanical stim-
uli, but might be involved in the formation of mechano-
sensory complexes with other yet to be identified sensory
proteins.
Ca2+ dependent modulation
Ca2+ is one of the most important endogenous modulators of
TRPA1. It mediates both potentiating (activating) and
Pflugers Arch - Eur J Physiol (2012) 464:425–458
inactivating (desensitizing) effects that are still not fully
understood. TRPA1 is affected by [Ca2+]e that can be
entirely attributed to entry through TRPA1 and subsequent
elevation of intracellular calcium. The mutation of Asp918
in the putative TRPA1 pore greatly reduces Ca2+ permeabil-
ity. Extracellular Ca2+ alone produced neither potentiation
nor inactivation. Both processes were restored by reducing
intracellular Ca2+ buffering. Application of Ca2+ to the
cytosolic face of excised patches is sufficient to produce
both potentiation and inactivation of TRPA1 channels.
Moreover, in whole cell recordings, elevation of intracellu-
lar Ca2+ potentiated, but did not inactivate TRPA1. Thus,
potentiation and inactivation are two independent processes.
TRPA1 currents could be inactivated by Mg2+, Ba2+ and
Ca2+, but potentiating effects were only observed for Ba2+
and Ca2+ [289].
Phosphatidylinositol-(4, 5)-bisphosphate-dependent
modulation
Most if not all TRP channels are regulated by phosphatidyl-
inositol-(4, 5)-bisphosphate (PI(4, 5)P2) that causes channel
activation or sensitization, while depletion of PI(4, 5)P2, e.g.
via PLC-dependent mechanisms, renders TRP channels
inactive [209]. The situation for TRPA1 is not completely
clear. A typical feature of TRPA1 is its rapid desensitization
following activation by agonists such as MO, cinnamalde-
hyde, and a high intracellular Ca2+ concentration. TRPA1
desensitization is delayed when PI(4, 5)P2 is supplyed via
the patch pipette whereas neomycin, a PI(4, 5)P2 scavenger,
accelerates desensitization. Preincubation with the
phosphatidylinositol-4-phosphate-5-kinase (PI-4 kinase)
inhibitor wortmannin reduces both constitutive TRPA1
channel activity and the response to MO. This set of data
confirm that PI(4, 5)P2 modulates TRPA1, albeit to a lesser
extent than other known PI(4, 5)P2-sensitive TRP channels,
such as TRPM4 [135]. Other reports show that in inside-out
patches, PI(4, 5)P2 does not activate TRPA1. When TRPA1 is
activated by electrophilic agonists, addition of PI(4, 5)P2
produced a concentration-dependent inhibition of TRPA1.
Apparently, PI(4, 5)P2 may act as an inhibitor of TRPA1,
reducing its sensitivity to activators [140].
This view is further complicated by a possible TRPV1/
TRPA1 interaction. In DRG neurons, hydrolysis and accu-
mulation of PI(4, 5)P2 modulate both TRPV1 and TRPA1
activities. Inflammation results in a long-lasting PI(4, 5)P2
depletion. A chronic PI(4, 5)P2 production can be stimulated
by overexpression of PI-4 kinase, while the PI(4, 5)P2 -
specific phospholipid 5′-phosphatase can reduce plasma
membrane levels of PI(4, 5)P2. However, agonist responses
of TRPA1 are not significantly influenced by chronic
changes in PI(4, 5)P2. However, when TRPA1 and TRPV1
are present, chronic PI(4, 5)P 2 reduction leads to
437
pronounced tachyphylaxis of both channels. Thus, chronic
effect of PI(4, 5)P2 on TRPA1 activity depends on presence
of the TRPV1 [220], and the possible formation of mixed
TRPV1-TRPA1 oligomers whose regulation differs from
that of the single channels.
Modulation by phosphorylation and polyphosphates
TRPA1 is likely to be modulated by phosphorylation. It is
known that TRPA1 can be activated by bradykinin [23].
This process involves activation of PKA, that depends on
cyclic AMP (cAMP) and probably induces channel phos-
phorylation and sensitization [8, 291].
One difficulty to study effects of phosphoinositides in
detail, like PI(4, 5)P2, is represented by the need to take long
recordings in inside-out configurations. Probably, the function
of TRPA1 requires an unidentified cytosolic factor whose
action can be mimicked by inorganic polyphosphates. Poly-
phosphates (e.g. pyrophosphate (PPi), polytriphosphates
(PPPi)) are intracellular molecules that are known to be able
to rescue activation of TRPA1 by covalent modification in
inside-out patches [139]. It has been postulated that TRPA1
can switch from a conformation insensitive to pungent chem-
icals to a sensitive one, or, alternatively, that TRPA1 becomes
completely non-functional and insensitive to all activators
when the cytosolic factor is absent. In this scenario, polyphos-
phates could stabilize the inside- out patch configuration, a
view supported by the observation that Ca2+ fails to activate
TRPA1 in inside-out patches unless polyphosphates are
present. Therefore, TRPA1 might exist in different func-
tional states: a native state (cell-attached patch) and a
non-native state (excised patch). Interestingly, THC can
activate TRPA1 even in the absence of polyphosphates,
whereas electrophilic pungent chemicals and Ca 2+
require polyphosphates for activation [49].
Modulation by protein—protein interaction
Interactions of TRP channels with diverse modulatory pro-
teins or even β-subunits are an increasingly important
research topic. So far, the best studied TRPA1 partners are
TRPV1, the ubiquitin hydrolase CYCL, the PKA anchor
protein AKAP5 and secretogranin 3, a member of the chro-
mogranin/secretogranin family of neuroendocrine secretory
proteins that serve as precursors for biologically active
peptides (see also http://trpchannel.org/).
Some features of neuronal TRPA1 are not present in het-
erologous expression systems but can be restored when
TRPA1 and TRPV1 channels are co-expressed [243]. TRPV1
and TRPA1 function together and resiniferatoxin-mediated
“neurosurgery” removes both sensor elements. In adult mice,
resiniferatoxin causes desensitization to heat and sensitization
to cold, resulting in cold hyperalgesia [223]. Ca2+-triggered
438
activation of TRPA1 is attenuated by the presence of TRPV1
in the presence of extracellular Ca2+ but not in Ca2+-free
conditions. TRPV1 mutations at Tyr671 probably affect
TRPA1 permeation properties, but the mutations in TRPV1
do not affect association of TRPA1 and TRPV1 channels. The
mutation of Tyr671 to lysine in TRPV1 altered the magnitude
of currents through TRPA1, the sensitivity of [Ca2+]e and the
voltage-dependency [221]. The synthetic cannabinoid,
arachidonoly-2 chloroethanolamine (ACEA) activates
TRPV1, but inhibits TRPA1 probably via a TRPV1-
dependent mechanism. Some cannabinoids mediate their
peripheral analgesic properties, at least in part, via the TRPV1
and TRPA1 channels [240].
Analysis of icilin effects on TRPA1 and sensitivity of
mice to cold stimuli, which is inhibited by blockers (BEL,
bromoenol lactone) of the sub-type of phospholipase A2,
iPLA2, has suggested a possible interaction of TRPA1 with
this lipase [102]. The mammalian prokineticins PK1 and
PK2, and their G-protein coupled receptors prokineticin
receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) have
been identified and linked to several biological effects as gut
motility, neurogenesis, angiogenesis, circadian rhythms,
hematopoiesis, and nociception. Mice lacking PKR genes
exhibit impaired PK1, PK2 mediated hyperalgesia, which
partially depend on TRPA1. Both receptors may interact
with TRPA1 [207]. Another link between pain and TRPA1
comes from studies on the protease activated receptor 2,
PAR2. TRPA1 is functionally coupled with PAR2 and both
proteins are co-localized in DRG. PAR2 activation poten-
tiates TRPA1 activation probably via PLC. Application of
phospholipase C (PLC) inhibitors or phosphatidylinositol-
4,5-bisphosphate PI(4, 5)P2 suppressed this potentiation
indicating that PI(4, 5)P2 might be a TRPA1 inhibitor rather
than an activator. This effect is probably mediated via a
coupling between TRPA1 and PAR2 [63, 314].
A dietary link to TRPA1 modulation
A huge number of TRPA1 modulators are naturally produced
in plants, fungi and animals to induce avoidance behavior in
predators or competitors. The best known examples are the
many culinary plants that produce structurally unrelated pun-
gent or irritating compounds
Allium sativum (garlic) has the enzymatic machinery to
generate the pungent electrophilic allicin [174], an organo-
sulfur compound that acts as a precursor for a host of
compound that includes diallyl sulphide, diallyl disulfide
and diallyl trisulfide. In a similar way, allyl isothiocyanates
can be generated from wasabi, horse radish and mustard oil.
These compounds are pungent and cause inflammations,
edemas and hyperalgesia [129]. Garlic, and particularly
allicin, protect against the development of right ventricular
hypertrophy and reduces right ventricular pressure [263].
Pflugers Arch - Eur J Physiol (2012) 464:425–458
This protective effect is due to an action on vascular endo-
thelium preventing endothelial cell dysfunction. Boiled or
aged garlic, which cannot generate allicin from its amino-
acidic precursor due to enzymatic denaturation, has no pro-
tective effect and is non-pungent. Since TRPA1 is expressed
in heart, it is intriguing to speculate that this channel might
be contributing to these beneficial effects [259].
The spice wasabi (from Wasabia japonica) acquires pun-
gency not only by AITC, but also by related isothiocyanates
[6-(methylsulfinyl)hexyl isothiocyanate (6-MSITC) and 6-
(methylthio)hexyl isothiocyanate (6-MTITC)], that are less
pungent but contribute to the fresh flavor of wasabi. All
these isothiocyanates activate TRPA1 in an electrophilic
manner [282].
Another interesting compound from garlic, ajoene, is an
unsaturated compound that contains a reactive thiophilic
disulfide bond, and that acts as antithrombotic (anti-clotting)
agent. Ajoene cannot directly activate TRPA1, but it can
enhance activation of TRPA1 by electrophiles, potentiating
the depolarization that they induce [309].
The drimane sesquiterpenes isovelleral and polygodial
are noxious and pungent terpenes characterized by reactive
α,β-unsaturated 1,4-dialdehyde moiety. These small mole-
cules of fungal and animal origin are all TRPA1 agonists
[88],and are the archetypal members of a large class of
dialdehydes that also includes miogadial (MD), miogatrial
(MT), and polygodial (PG), and that show equal or even
stronger TRPA1 agonistic activity than AITC from MO
[126]. Miogadial, isolated from flower buds of the myoga
ginger (Zingiber mioga) or from water pepper (Polygoman
hydropiper) has a pleiotropic biological profile that includes
antimicrobial activity against Gram-positive bacteria and
yeasts as well as chemopreventive potentials. Leaves of
water pepper contain polygodial that elicits a warm and
pungent flavour. Polygodial has strong antifungal and anti-
microbial activities and acts as anti-hyperalgesic, anti-
nociceptive, anti-inflammatory, anti-allergic agent and vaso-
relaxant agent [10]. The related sesquiterpene isovelleral,
isolated from the fungus Lactarius vellereus, render it ined-
ible because of its peppery taste. Isovelleral contains a β-
unsaturated dicarbonyl moiety potentially capable of form-
ing Michael adducts. Interestingly, it can also activate
TRPA1 with mutations of reactive cysteines. Thus, dialde-
hyde sesquiterpenes may activate TRPA1 through a mecha-
nism that differs from other electrophiles [20]. Interestingly,
some of these compounds are also activators of TRPV1 (see
for a review [286]).
The main pungent component in galangal (Alpinia gal-
angal) is 1′-acetoxychavicol acetate (ACA). ACA does not
interact with TRPV1, but activates TRPA1 with a potency
higher than MO [201]. Galangal has an interesting ethno-
pharmacology that includes stimulation of the appetite, pro-
motion of the blood circulation in the brain and stregthening
Pflugers Arch - Eur J Physiol (2012) 464:425–458
of sexuality. When consumed in large amounts, it can also
generate visual hallucinations.
Cinnamaldehyde from Cinnamonum verum is the main
constituent of cinnamon oil. It is widely used as a spice in
cookery as a condiment and flavoring material in chocolate
and many dessert recipes, such as apple pie, donuts, and
spicy candies. Interestingly, oral application of cinnamalde-
hyde causes burning and tingling due to activation of
TRPA1 [14, 20].
Szechuan peppers from various Zanthoxylum species and
the Japanese pepper tree (Z. Piperitum, sansho) contain a
mixture of alkamides that includes hydroxy-α-sanshool, a
compound that causes irritations, cooling, tingling and
sometimes paresthetic sensations on the tongue and strongly
stimulates salivation [189]. Hydroxy-α-sanshool but not
hydroxy-β-sanshool depolarizes sensory neurons with con-
comitant firing of action potentials and evokes inward cur-
rents due to activation of TRPA1 and TRPV1 [153].
Additionally, hydroxy-α-sanshool activates a subset of sen-
sory DRG neurons by inhibiting 2-pore potassium channels,
KCNK3, KCNK9, KCNK18 [25]. A tingle-evoking san-
shool analog, isobutylalkenyl amide (IBA), excites rat
DRG neurons and causes unfamiliar aversive sensations
probably mediated by activation of TRPM8, TRPA1 and
TRPV1 [146]. Interestingly, Szechuan pepper also contains
an abundant acyclic terpene alcohol, linalool, which also
activates TRPA1. Linalool, as well as 6-shogaol and 6-
paradol from ginger (Zingiber officinale), act on TRPA1
by covalent bonding whereas none of these compounds
activated TRPV1 with this mechanism [237].
Curcumin, the active principle of turmeric root (Curcuma
longa), is used in many cusines as “yellow curry”. It pro-
vides pain relief, probably by TRPA1 induced slow depola-
rization followed by Na+ channel inhibition in sensory
ganglia and/or fast desensitization of the channel after acti-
vation [164]. Numerous clinical trials in humans are under-
way, studying the effect of curcumin on various diseases,
including multiple myeloma, pancreatic cancer, myelodys-
plastic syndromes, colon cancer, psoriasis, and Alzheimer’s
disease and the compound might have interesting applica-
tion in oncology, both as a selective cytotoxic agent, and in
cancer supportive care [114].
Perilla frutescens from the Lamiaceae family is a food
plant widely used in Asian cuisine known for its interesting
taste also called beefsteak plant, Chinese basil, purple mint
or rattlesnake weed. The red perilla is used mostly in fish
stews in China whereas the green one is more commonly
found in Korean and Japanese cuisines as pickled green
perilla with red chili powder and soy sauce. The active
compounds in perilla, perillaldehyde and perillaketone, are
both activators of TRPA1. Perilla leaves (zisuye) are widely
used in traditional Chinese medicine as a remedy against
stomach dysfunction [22].
439
From the berries of black pepper (Piper nigrum) 19
compounds that are TRPV1 and TRPA1 activators have
been characterized. Dried pepper corn has been used since
antiquity for both its flavour and as a medicine. Piperine
(causing the spiciness of black pepper), isopiperine, isocha-
vicine, piperanine, piperolein A, piperolein B, and N-
isobutyl-(2E,4E)-tetradeca-2,4-diamide also strongly acti-
vate both TRPA1 and TRPV1 [216].
The thyme plant (Thymus vulgaris) contains thymol (also
known as 2-isopropyl-5-methylphenol), is a natural mono-
terpene phenol derivative of cymene isomeric with carva-
crol. Thymol has a pleasant aromatic odor with a relatively
pungent flavor, and is often used to flavour meats, soups and
stews. Thymol is a member of natural compounds known as
biocides that have strong antimicrobial and antifungal prop-
erties. Thymol, as well as closely related carvacrol derived
from Origanum vulgare, can reduce bacterial resistance to
antibiotics. Additionally, there is growing evidence that
thymol has antitumor properties. Thymol directly activates
TRPA1 and sensitizes it to further exposure to thymol and
carvacrol [165, 306]. The response to thymol is blocked by
camphor [165]. Thymol-related phenols such as 2-tert-
butyl-5-methylphenol and 2,6-diisopropylphenol (propofol)
also activate TRPA1 [306].
Salvia officinalis is used as a traditional herbal medicine
for gastric disturbances and inflammatory processes. Hydro-
alcoholic extract (HE) from salvia leaves, containing carno-
sol and ursolic acid/oleanolic acid, presents significant anti-
inflammatory and also antinociceptive effects very likely
through modulation of TRPA1 [238].
The California bay laurel Umbellularia californica can
be used in cuisine as a replacement of laurel (Laurus nobilis
L.), but has also been nicknamed ‘the headache tree’
because inhalation of its vapours can cause severe headache
crises. The mechanism of the headache precipitating proper-
ties of Umbellularia californica has recently been clarified
and traced to the presence of elevated concentrations of the
monoterpene ketone umbellulone, a reactive compound that
rapidly binds thiols, shows irritating properties, and can
stimulates TRPA1 [205, 322].
Ligustilide, the major aroma constituent of celery (Apium
graveolens), is an electrophilic volatile dihydrophthalide
that activates TRPA1 but is also capable of inducing a
modest block of activated TRPA1. The action of ligustile
on TRPA1 contributes to the gustatory effects of celery, its
major dietary source, and to the pharmacological action of
popular plants used in traditional Chinese (Angelica
sinensis, Ligusticum chuanxion) and native American
(Ligusticum portiere) medicine [323].
A characteristic astringent taste is the gustatory hallmark
of polyphenols and tannins. Catechins and their polymers
are the most abundant polyphenols in wine and tea. A
typical green tea polyphenol is epigallocatechin gallate
440
(EGCG). EGCG activates TRPA1 and might play an impor-
tant role in the astringency taste on the tongue [158]. Oleo-
canthal, an anti-inflammatory compound contained in extra-
virgin olive oil, elicits an unusual oral pungency sensed
almost exclusively in the throat. This rare irritation pattern
is a consequence of both the specificity of oleocanthal for a
single sensory receptor, and the anatomical restriction of this
sensory receptor to the pharynx, within the oral cavity.
Oleocanthal selectively activates TRPA1 but not TRPV1.
The over-the-counter analgesic, ibuprofen, which elicits the
same restricted pharyngeal irritation as oleocanthal, also
specifically excites rodent sensory neurons via TRPA1
through a mechanism that is different from the covalent
cysteine modification [226].
Eugenol from cloves (Szygium aromaticum) is a phenyl-
propene used in perfumeries, flavorings (very strong taste),
and medicine as a local antiseptic and anesthetic. Similar
properties are shown by gingerols, a class of pungent com-
pounds from fresh ginger (Zingiber officinale). Both eugenol
and gingerol activate TRPA1 channel [20]. Interestingly, some
analogues of gingerols are potent TRPA1 antagonists [194].
Resolvins are synthesized in the human body from a fish
oil derived omega-3 fatty acids eicosapentaenoic acid (EPA)
and docosahexaenoic acid (DHA). Resolvin D1 (RvD1), a
naturally occurring anti-inflammatory and pro-resolving
lipid molecule inhibits TRPA1 at nanomolar and micromo-
lar levels. Consistent attenuations can be observed in
agonist-specific acute pain behaviours. RvD1 is a novel
endogenous inhibitor for several sensory TRPs such as
TRPA1, TRPV3 and TRPV4 [17].
Other TRPA1-active natural compounds such as caffeine,
nicotine, menthol and camphor had already been discussed
in previous sections.
Physiological functions of TRPA1
Sensory functions
As already described in the previous sections, TRPA1
mainly acts as a chemosensor involved in nociception.
Interestingly, during development, TRPA1, similarly to
other TRP channels, emerges in waves of differentiation.
This process starts at embryonic day 12.5 (E12.5) and
extends into the postnatal life. Most likely, TRPA1-
expressing sensory neurons derive from the population of
TRPV1-expressing neurons, and form two distinct classes of
nociceptors: around birth in the peptidergic population, and
after P14 in the nonpeptidergic class [120].
TRPA1 is a typical sensor of cell threat. Sensing of
TRPA1 activating compounds can provide warning of
potential damage rather than actual damage itself. Many
TRPA1 activators are also lachrymators in the eye, which
Pflugers Arch - Eur J Physiol (2012) 464:425–458
would thus sense toxic and irritant compounds, such as α-
terpineol, amyl acetate, benzaldehyde, and toluene, before
they reach the upper airways [28–30].
TRPA1 is necessary for development of inflammatory
hypersensitivity and its activity is functionally modulated
by growth factors that regulates sensitivity of sensory neu-
rons such as the nerve growth factor (NGF), the glial cell
line-derived neurotrophic factor (GDNF) and artemin, a
neuronal survival and differentiation factor. Short-term
application of artemin inhibits TRPA1 and plays a role in
the regulation of sensory neurons for nociception [313].
However, overexpression of artemin enhances expression
of TRPA1 in sensory neurons. This situation occurs in
chronic inflammation and causes an increased sensitivity
noxious cold [86, 180].
Thermoregulation
TRPA1 agonists enhance thermogenesis and inhibit heat
diffusion [182]. Icilin, a TRPM8/TRPA1 agonist, produces
a dose-related hyperthermia in rats which requires both NO
production and NMDA receptor activation. However, it is
difficult to differentiate between the role of TRPM8 and
TRPA1 [70]. TRPA1 activation alone also causes hyper-
thermia [235]. Different to TRPV1 inhibitors, the selective
blockade of TRPA1 channel attenuates pathological pain
without altering noxious cold sensation or causing hypo-
thermia [51]. Thus, TRPA1 activation seems to have a mild
effect on global thermoregulation.
Cell barrier function
TRPA1-expressing vagal sensory afferents innervating air-
ways and abdominal tissues mediate axonal chemosensitiv-
ity and control of neuropeptide release. The activation of
TRPA1 evokes CGRP release and becomes important dur-
ing increasing vascular permeability in inflammation or
neuropathy [299].
Gastro—intestinal system
TRPA1 plays a role in the gastric accommodation (or gastric
relaxation) response that reduces meal-induced increase in
gastric pressure and thus might impair the development of
dyspeptic symptoms. Pretreatment with TRPA1 agonist
increases the gastric tone via a TRPA1-mediated cholinergic
neuronal pathway and subsequently inhibits meal-induced
gastric accommodation [154].
The effect of satiety might also be partially related to
activation of TRPA1. Selective TRPA1 agonists from spices
may act within cranial visceral afferent pathways mediating
satiety and contribute to reduction of the food intake asso-
ciated with spicy diets [55].
Pflugers Arch - Eur J Physiol (2012) 464:425–458
TRPA1 also has an influence on GI motility. Secretory
effects are induced by TRPA1 agonists. Mucosal application
of agonists also induced Cl- and HCO3- secretion in a
concentration-dependent manner whereas the serosal appli-
cation has no effect. TRPA1 activation induces anion secre-
tion through PG synthesis, independently of neural
pathways in the colon, and is mediated mainly by the PG
receptor EP4 subtype. Activation of TRPA1 in colonic epi-
thelial cells is also involved in the host defense mechanism
through rapid anion secretion [131].
Serotonin is abundantly present throughout the GI and is
stored mostly in enterochromaffin (EC) cells located on the
mucosal surface. Secretion of serotonin from EC cells stim-
ulates both intrinsic and extrinsic nerves, which results in
various physiological and pathophysiological responses,
such as GI contractions. TRPA1 is highly expressed in EC
cells. TRPA1 agonists stimulate EC cell functions by an
increased serotonin release, which subsequently promotes
ileum contraction via the serotonin receptor. Thus, TRPA1
acts as a sensor molecule for EC cells and regulates GI
function [212].
Cardiovascular system
As TRPA1 is expressed in most endothelial cells and in
arterial vessels, it is involved in regulation of the blood flow.
It is probably localized and functional at the myoendothelial
interface [233]. Activation of TRPA1 mediates endothelium-
dependent smooth muscle cell hyperpolarization and vaso-
dilatation that requires the activity of small and intermediate
conductance Ca2+ -activated K+ channels. TRPA1 agonists
cause transient depressor responses followed by sustained
increases in heart rate and blood pressure that may result from
elevated sympathetic nervous activity. These findings indicate
that TRPA1 activity influences vascular function [79]. Gaso-
transmitters such as hydrogen sulphide causes vasodilation
probably via relase of CGRP, a mechanism similar as that
described for TRPV1 [300].
Pancreas
As described above, TRPA1 is expressed in pancreatic β-cells.
Activation of TRPA1 by AITC, H2O2, 4-hydroxynonenal (4-
HNE), and cyclopentenone prostaglandins (PGJ2) and a novel
agonist methylglyoxal (MG) induces membrane currents, depo-
larization, and Ca2+ influx leading to generation of action
potentials. Endogenous and exogenous ligands of TRPA1 cause
Ca2+ influx and induce basal insulin release in pancreatic β-
cells. TRPA1-mediated depolarization acts synergistically with
KATP channel blockade to facilitate this process [45]. In addi-
tion, the increase in intracellular Ca2+ concentration seems to be
due to an influx through the L-type voltage-dependent Ca2+
channels activated upon depolarization induced by electrophilic
441
activation of TRPA1. Thus, TRPA1 appears to be functionally
coupled with the L-type voltage-dependent Ca2+ channel and
ultimately mediate insulin secretion [213].
Bladder
TRPA1 is present on unmyelinated nerve fibers within the
urothelium, suburothelial space, and muscle layer as well as
around blood vessels throughout the bladder. TRPA1 ago-
nists increased micturition frequency and reduce the voiding
volume. Similar changes in urodynamic parameters are also
observed after disruption of the urothelial barrier with prot-
amine sulfate. Intravesical TRPA1 activators initiate detru-
sor overactivity, indicating that TRPA1 has a role in sensory
transduction in this organ.
Acrolein, which can be formed endogenously under con-
ditions of inflammation, and is also a toxic metabolite of
cyclophosphamide, are known activators of TRPA1 that
induce cystitis in the bladder. Similarly, H2S is a TRPA1
activator potentially involved in inflammatory bladder dis-
ease [261]. Other examples are fatty-acid derived nitroal-
kenes that react with nucleophiles such as cysteine and
histidine residues in a variety of susceptible proteins, includ-
ing TRPA1. They activate TRPA1 on afferent nerve termi-
nals in the urinary bladder and thereby increase bladder
activity [11]. Thus, pathologic activation of TRPA1 may
play a role in inflammation of the bladder. Future studies
should therefore address a potential regulation of bladder
TRPA1 in cystitis and the relative potential of TRPA1 ver-
sus TRPV1 ligands to treat cystitis-associated signs and
inflammation symptoms [190, 261].
Importantly, patients with lesions in the central nervous
system exhibit a voiding reflex after perfusion of the bladder
with cold solutions (ice water), which is absent in healthy
volunteers. The role of TRPA1 in this phenomenon needs to
be urgently evaluated because of its importance to differ-
entiate peripheral from central bladder dysfunction. Patients
without neurological diseases have a heightened cold blad-
der perception during the ice water test than patients with
neurological diseases [5, 67].
TRPA1 in other animal models
In C. elegans, genetic approaches show that mutations in
trpa-1 cause specific defects in mechanosensory behaviors
related to nose-touch responses and foraging [145]. In addi-
tion, PVD neurons, mulitidendritic nociceptors in the body
wall of C. elegans with long undifferentiated processes,
express TRPA1 that confers response to harsh touch and
also to cold temperatures [50].
The fruit fly expresses multiple TRPA channels. Drosophila
TRPA1s respond to reactive electrophilic compounds
442
leading to nociception (avoidance). The nociceptive function
of TRPA1s requires their expression in the nervous system,
specifically within nociceptive multi-dendritic (MD) sensory
neurons [206]. The Drosophila TRPA family member, pain-
less, is expressed in a subset of MD neurons in the larval
epidermis. This TRPA-type channel is required for larval heat
and mechanical nociception. Mutations of painless also results
in a defect in male-male courtship behavior and alteration in
olfaction sensitivity in adult flies [292]. Painless is also
expressed in the Drosophila heart and causes pauses in
heartbeat, mimicking the pressure-induced response. Thus,
painless might constitute part of a mechanosensitive path-
way that adjusts cardiac muscle activity and mediates cardiac
mechanotransduction [251]. Interestingly, painless isoforms
contain fewer ARDs than the canonical painless protein.
Those isoforms, that essentially lack ankyrin repeats, can
still perform mechanical nociception, but are not involved
in thermal nociception phenotypes. In contrast, isoforms
that contain ARDs are sufficient for thermal nociception
but are not capable of mechanical nociception [123].
Negative geotaxis in Drosophila (a movement of the fly
against gravity) requires Johnston’s organ, a mechanosen-
sory structure located in the cap cells of the antenna that also
detects near-field sound. The Johnston’s organ expresses
two TRPA genes, painless and pyrexia. Specific mutations
of these two TRPA genes disrupt negative geotaxis [264].
Larvae of fruit flies discriminate between the optimal
temperature of 18 °C and slightly higher temperatures
(19–24 °C). This discrimination requires the TRPA channels
that functions downstream of a PLC-dependent signaling
cascade similar to that used in fly phototransduction. This
signaling cascade promotes amplification of small differ-
ences in temperature and facilitates adaptation to temper-
atures within the comfortable range [161]. A small set of
warmth-activated anterior cell (AC) neurons located in the
fly brain play a critical role for temperature selection. AC
neuron activation occurs just above the fly’s preferred tem-
perature and depends on TrpA1. Flies that selectively
express trpa in the AC neurons select normal temperatures,
whereas flies in which TrpA1 function is reduced or elimi-
nated choose warmer temperatures. TRPA1 promotes avoid-
ance of slightly elevated temperatures and acts together with
a distinct pathway for cold avoidance to set the fly’s pre-
ferred temperature, a general strategy for robustly selecting
a narrow temperature range optimal for survival [112].
The discrimination among sensory stimuli is critical for
Drosophila survival, e.g. discrimination between “noxious”
chemicals or “innocuous” warming. This process requires
highly tuned TRPA channels. A specific TRPA1 isoform
in chemosensory neurons respond only to chemicals but
not to warmth that is sensed by another TRPA isoform.
Cell-type segregation of TRPA1 activity is critical: when
the thermosensory isoform is expressed in chemosensors,
Pflugers Arch - Eur J Physiol (2012) 464:425–458
flies respond to innocuous warming with regurgitation, a
nocifensive response. Drosophila TRPA1 orthologs pref-
erentially activated by heat have two portable heat-
sensitive modules within the ARD [59]. Heat-sensing
domains are encoded by specific exons of the TRPA1
locus. These exons are used for alternative splicing to
produce four TRPA1 isoforms, each with distinct temper-
ature thresholds [321].
TRPA1 isoform diversity is conserved in malaria mos-
quitoes, which may indicate that discrimination of host-
derived warmth and chemical repellents are differentially
sensed [132]. Heat sensitivity plays also a critical role in
close-range host-seeking behaviors of adult female Anoph-
eles gambiae, the principal Afrotropical vector for human
malaria. The Anopheles TRPA1 channel acts as a heat-
sensor in host-seeking adult female mosquitoes, and is
localized at the distal antennas that specifically respond to
temperature gradients [294].
Temperature discrimination via TRPA1 is also conserved
in other insects and especially in the honey bee. Honey bees
are relatively small heterothermic animals that are highly
susceptible to changes in ambient temperature. They are
able to maintain the brood nest temperature between 32 °C
and 36 °C either cooling or heating the nest. The honey bee
TRPA1 is activated by temperatures >34 °C as well as by
insect antifeedants like camphor. It is expressed in the
antennal flagellum, and ablation of the antennal flagella
and injection of TRPA inhibitors impair warmth avoidance
in honey bees. Gustatory responses of honey bees to sucrose
are suppressed by noxious heat and insect antifeedants,
but are relieved by TRPA inhibitors. Evolutionarily,
honey bees lost the ancient chemical sensor that is
homologous to Drosophila TRPA1. Its TRPA1 originates
from duplication of the TRP channel water witch, a
TRP channels providing hygrosensation together with
the TRPV homolog nan [148].
Gustatory receptor neurons (GRNs) in Drosophila also
express TRPA1 that responds to aversive compounds. Elim-
ination of TRPA1 had no impact on the responses to nearly
all bitter compounds tested, including caffeine, quinine, and
strychnine, but is essential for the behavioral and electro-
physiological responses to aristolochic acid. Aristolochic
acid is rather not a direct activator or inhibitor of TRPA1,
but leads to activation of PLC-dependent pathway [142].
Drosophila larvae also show food-averse migration toward
food-free habitats. This developmental switching from food
attraction to aversion is regulated by a neuropeptide Y
(NPY)-related brain signaling peptide. A fructose-responsive
chemosensory pathway, which requires painless, modulates
food-averse migratory and social behaviors [307].
Taken together, these data show that TRPA1 is critically
involved in insect thermal homeostasis and feeding. It is
therefore tempting to suggest that the profligacy of TRPA1
Pflugers Arch - Eur J Physiol (2012) 464:425–458
modulators of plant origin has its raison-d’être in the co-
evolutionary relationship between insects and plants.
Zebrafish has two TRPA1 paralogs. In this animal model
the role of TRPA1 in detecting thermal and mechanical
stimuli is controversial. The two zebrafish TRPA1 paralogs
are expressed in sensory neurons and are activated by sev-
eral chemical irritants in vitro. High-throughput behavioral
analyses of trpa1a and trpa1b mutant larvae indicate that
TRPA1b is necessary for behavioral responses to these
chemical irritants. However, both TRPA1 paralogs are not
required for behavioral responses to temperature changes or
for mechanosensory hair cell function in the inner ear or
lateral line. Zebrafish TRPA1 has a role in chemosensing but
not in thermal or mechanical sensing [232].
TRPA1 was likely a noxious heat and chemical receptor
and co-expressed with TRPV1 in the nociceptive sensory
neurons of ancestral vertebrates such as Western clawed
(WC) frogs and green anole lizards and later lost heat
activation [242].
Recently, snake TRPA1 has been related to infrared sens-
ing. Infrared signals are initially received by the pit organ, a
highly specialized facial structure that is innervated by nerve
fibres of the somatosensory system. How this organ detects
and transduces infrared signals into nerve impulses is not
known. Consistent with their role as primary transducers of
infrared stimuli, TRPA1 orthologues from pit-bearing
snakes (vipers, pythons and boas) are the most heat-
sensitive vertebrate ion channels identified so far [107].
The “infrared sensory gene” TRPA1 was sequenced in 24
snake species. Pit-bearing snakes contain an 11 aa domain
which is unique when compared with non-pit snakes and
other vertebrates, that might be potentially functionally
important for infrared sensing [101]. In another report, iso-
forms for infrared sensing show three parallel amino acid
changes in the central region of their ARDs [311]. An
intriguing question arises how the exceptional TRPA1 sen-
sitivity functions and what is the evolutionary origin of
these warmth-activated TRP channels [217].
TRPA1 in disease
TRPA1-related channelopathies
The only TRPA1 channelopathy described so far is a rare
pathological pain state. The autosomal dominant Familial
Episodic Pain Syndrome (FEPS) is characterized by epi-
sodes of debilitating upper body pain, triggered by fasting
and physical stress. Candidate gene sequencing identified a
point mutation that leads to substitution of Asn855 to Ser in
S4 of TRPA1. The mutant channel has a normal pharmacol-
ogy but shows a more than 5-fold increase in inward current
on activation at normal resting potentials. Patients have an
443
enhanced cutaneous flare response and secondary hyperalge-
sia to punctate stimuli. Specific TRPA1 antagonists inhibit the
abnormal in vitro response of the mutant TRPA1 channel,
promising a useful therapy for this syndrome [156, 303].
A single nucleotide polymorphism (SNP), which results
in the Glu179Lys substitution, has been found in pain
patients who experience paradoxical heat sensation [32]. In
contrast to wild type TRPA1 expressed in HEK293 cells,
which shows an higher protein expression in cold (4 °C) and
heat (49 °C)-treated cells and is responsive to cold stimula-
tion, the E179K variant is not activated by cold, possibly
due to the loss of ability to interact with other proteins or
defective heteromerization [186].
TRPA1 and pain
TRPA1 is an excellent candidate to explore and intricately
understand how single channel properties can tailor behav-
ioral nociceptive responses. Dermal application of electro-
philic TRPA1 activators can induce spontaneous pain, heat
and mechanical hyperalgesia, cold hyperalgesia and a neu-
rogenic axon reflex erythema (vasodilation) through direct
TRPA1 stimulation [96, 193, 200]. In general, also post-
operative pain is mainly caused by TRPA1 activation
[297]. Since it is also involved in persistent chronic
painful states such as inflammation, neuropathic pain,
diabetes, fibromyalgia, bronchitis and emphysema, as
well as in acute nociception, it provides an excellent
target for therapeutic pharmacological interventions (for
a review see [8, 98]).
Peripheral diabetic neuropathy (PDN) is a major compli-
cation of diabetes mellitus (DM). Pathogenesis of PDN
could be due to sustained activation of TRPA1 by ROS
and RNS compounds generated in DM. In diabetic rat and
mice models, the TRPA1 channel antagonist Chembridge-
5861528 reduced sustained activations of the TRPA1 chan-
nel, providing a selective disease-modifying treatment of
PDN [149, 296]. Similarly to DM, neuropathic pain can
also develop during chronic uremia. The highly reactive
compound methylglyoxal (MG) accumulates in all cells, in
particular neurons, and leaks in the plasma. It is known that
MG covalently modifies arginine, lysine and cysteine resi-
dues and forms advanced glycation end products, leading to
hyperglycemia-induced tissue damage [40]. The electro-
philic structure of the cytotoxic ketoaldehyde MG strongly
suggests TRPA1 as a molecular target, also because this
compound shows thiol-trapping properties. MG cause neu-
ropathic pain in several metabolic disorders and is also
considered as a promising target for medicinal chemistry
[81].
Cancers cause excruciating pain that severely reduces the
quality of life in cancer patients. The nerve growth factor
(NGF) plays a cardinal role in inflammation and pain,
444
interacting with multiple pro-inflammatory cytokines. It is
highly elevated in human oral squamous cell carcinoma
tumors where it acts as a key endogenous molecule involved
in cancer-related inflammation. NGF blockade decreases
tumor proliferation and nociception. Importantly, NGF
blockade also decreases the expression of TRPA1 [310].
TRPA1-caused pain is enhanced by neurotrophic factors
(NTFs). Both brain-derived neurotrophic factor (BDNF)
and glial cell-derived neurotrophic factor (GDNF) levels
are altered in pathological pain states, and exogenous BDNF
and GDNF have multiple effects on pain behavior, depend-
ing on the animal model (i.e. inflammatory vs. neuropathic).
BDNF and GDNF leads to enhanced expression and activity
of TRPA1 and subsequently to enhanced neuronal sensitiv-
ity to painful stimuli [57].
TRPA1 is also critically involved in pain induced by anti-
cancer treatment with platinum-based anticancer drugs, oxa-
liplatin and cisplatin, which produces early-developing, pain-
ful, and cold-exacerbated paresthesias. Oxaliplatin and
cisplatin evoked glutathione (GSH)-sensitive relaxation,
mediated by TRPA1 stimulation and the release of CGRP
from sensory nerve terminals, leading to either oxaliplatin-
evoked mechanical and cold hypersensitivity or cisplatin-
evoked mechanical allodynia [203]. Antimitotic drugs, such
as paclitaxel, also cause peripheral neuropathy. Application of
paclitaxel stimulated ROS formation that potentiates TRPA1
activation. These effects are prevented by N-acetyl-cysteine (a
reducing agent), GSH and HC030031 [183].
The NGF receptor TrkA diversifies into peptidergic and
non-peptidergic nociceptors around birth. In this process,
peptidergic neurons maintain TrkA expression, while non-
peptidergic neurons downregulate TrkA and upregulate the
common BDNF family ligand receptor Ret and bind IB4.
Ret is expressed in two distinct populations of small-
medium sized non-peptidergic neurons and is a critical
regulator of TrpA1. Ret-deficient mice fail to respond to
TRPA1-agonist induced neurogenic inflammation [94].
TRPA1 is also involved in endothelin-1 (ET-1)-induced
spontaneous pain-like behavior in mice. TRPA1 antagonists,
HC-030031 and AP18, significantly reduced the pain-like
behavior caused by ET-1 [169].
Another link between pain and TRPA1 comes from stud-
ies on the protease activated receptor 2, PAR2. Proinflam-
matory agents such as trypsin and mast cell tryptase cleave
PAR2 causing activation of this receptor that is also
expressed in sensory nerves. TRPA1 is functionally coupled
with PAR2. Both proteins are co-localized in DRG where
activation of PAR2 increased the TRPA1 currents [63].
Cytochrome-P450 (CYP450) epoxygenases metabolise
arachidonic acid (AA) into four different biologically active
epoxyeicosatrienoic acid (EET) regioisomers. Three of the
EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed
by the enzyme soluble epoxide hydrolase (sEH). sEH plays an
Pflugers Arch - Eur J Physiol (2012) 464:425–458
important role in nociception during peripheral inflammation.
sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-
EET-levels. 8,9-EET sensitizes TRPA1 expressing neurons
and elevates mechanical hyperalgesia. sEH knockout mice
show increased nociceptive responses to mechanical stimula-
tion in inflammation and 8,9-EET injection reduced mechan-
ical thresholds in naive mice. Thus, sEH can regulate
mechanical hyperalgesia during inflammation by inactivating
8,9-EET [34]. 5,6-EET levels increased in dorsal root ganglia
(DRGs) and the dorsal spinal cord, and 5,6-EET is released
from activated sensory neurons in vitro and enhances the
frequencyof spontaneous EPSCs (sEPSCs) in lamina II neu-
rons in SG by TRPA1 activation. 5,6-EET presynaptically
facilitated spinal cord synaptic transmission by TRPA1 caus-
ing mechanical allodynia [255].
TRPA1 is also a novel pain target in dorsal horn neurons
and sensory nerve endings in the SG. Blockade of the spinal
TRPA1 channel attenuates mechanical pain hypersensitivity
particularly to low-intensity stimulation in various patho-
physiological conditions. Blockade of the spinal TRPA1
channel reduced cutaneous neurogenic inflammation, pre-
sumably by decreasing the drive of spinal interneurons that
induce a proinflammatory dorsal root reflex. Thus, the spi-
nal TRPA1 channel also provides a promising target for
development of a selective disease-modifying therapy for
central pain hypersensitivity [224]. Indeed, proximal nerve
endings within the spinal dorsal horn require the TRPA1
regulated transmission to spinal interneurons that is
involved in pain hypersensitivity. Intrathecal administration
of Chembridge-5861528 attenuates pain hypersensitivity in
various experimental models (e.g. spinal nerve ligation and
rapid eye movement (REM) sleep deprivation). The spinal
TRPA1 channel provides a promising target for the selective
attenuation of a central mechanism contributing to patho-
physiological pain [298]. Selective TRPA1 receptor antag-
onists were also studied in an osteoarthritic (OA) rat model.
Blockade of TRPA1 disrupts transmission of high-intensity
mechanical stimulation to the spinal cord in OA rats and
reduces pain [187].
An important antianalgesic principle has been recently
discovered. Activation of TRPA1, e.g. by electrophilic qui-
none metabolites of acetaminophen (paracetamol) induces
deplolarizations in sensory nerves, thereby inactivating
voltage-dependent Na+ channels and attenuating action
potential firing. This provides an antinociceptive effect even
for some, probably slow, TRPA1 agonists [2]. Etodolac, a
nonsteroidal anti-inflammatory drug, attenuates mechanical
allodynia in a mouse model of neuropathic pain by a mech-
anism that is independent of cyclooxygenase inhibition.
However, it is also shows a selective TRPA1 agonist action,
providing evidence that etodolac desensitizes nociceptors or
inhibiting action potential firing by selective activation of
TRPA1 [125].
Pflugers Arch - Eur J Physiol (2012) 464:425–458
It is now well established that TRPA1 mediates head-
ache by dural mechanisms. TRPA1 on meningeal nerve
endings causes environmental irritant-induced headache,
but is also involved in migraine. TRPA1 is expressed on
a substantial fraction of dural afferents sensory nerve
fivers and activation of meningeal TRPA1 produces
behaviors consistent with those observed in migraine
attacks. Activation of meningeal TRPA1 via endogenous
or exogenous mechanisms can lead to afferent signaling
and headache [82].
TRPA1 in inflammation
TRPA1 is a main player in the fast onset and maintenance of
inflammation (Fig. 4). Many TRPA1 activating compounds
are produced during inflammation as results of lipid oxy-
dation, peroxide formation, and oxidative stress ([281], see
also previous sections).
The pathogenesis of the common chronic cutaneous vas-
cular disorder rosacea requires polymodal activation of
TRPA1, including cold, pungent products from plants and
spices, ROSs, and mechanical stimuli [13]. Moreover, acti-
vation of TRPA1 in the skin, e.g. in epidermal keratinocytes
enhances the expression of proinflammatory cytokines,
including IL-1α and IL-1β, which are known to be key
contributors to skin inflammation [12].
TRPA1 activation causes the release of CGRP and sub-
stance P which are involved in the induction of neurogenic
inflammation associated with the pain. Via this mechanism,
TRPA1 causes vasodilation and induces edemas, a key symp-
tom in inflamed tissue [157, 254]. Inflammation is mediated
by TRPA1 via an elevation of TNFα which is a key player in
Fig. 4 Contribution of TRPA1
activation to inflammatory
signaling pathways. TRPA1 and
TRPV1 are sensitized or
activated upon GPCR-PLC
receptor activation pathways .
Rise of intracellular Ca2+ levels
through IP3-dependent ER-
store release and/or TRPA1 and
TRPV1 permeation is required
for activation of TRPA1 and
triggers release of proinflam-
matory neuropeptides such as
substance P or CGRP. Phos-
phorylation through PKC and
other kinases also affects TRP
channel activity during inflam-
mation (adapted from [28] with
permission)
445
joint inflammation. Blockade of TRPA1 receptors may be
beneficial in reducing chronic pain in arthritis [91].
Lipogenase enzymes, such 12-LOX, generate lipid spe-
cies that are involved in inflammatory hyperalgesia. In
particular,hepoxilins HXA[3] and HXB[3] are increased
during peripheral inflammation, and promote initiation of
facilitated nociceptive processing through direct activation
of TRPV1 and TRPA1 at central terminals [109].
TRPA1 and itch
Some irritating sensations are mediated by TRPA1, but are
different from pain. Itch, the unpleasant sensation that evokes
a desire to scratch, accompanies numerous skin and nervous
system disorders, sometimes insensitive to antihistamine treat-
ment. Members of the Mas-related G protein-coupled receptor
(Mrgpr) family are activated by mast cell mediators and
promote histamine-independent itch. MrgprA3 and MrgprC11
act upstream from TRPA1. Interestingly, TRPA1 is a target of
both, MrgprA3 and MrgprC11, and is required for Mrgpr-
mediated signaling. TRPA1-deficient mice display little or no
scratching in response to pruritogens, indicating that TRPA1
is an essential component of the signaling pathways that
promote histamine-independent itch [302].
TRPA1 induces itch upon oxidative stress. Intradermal
injection of H2O2 or tert-butylhydroperoxide (tBHP) into
the nape of the neck in mice induces itch which is not
histamine dependent. Because resiniferatoxin treatment
abolished oxidant-induced scratching, it is suggested that
oxidative stress acts via C-fibers. Importantly, antioxidants
and TRPA1 antagonists may be used to treat human itch
conditions associated with oxidative stress [170].
446
TRPA1 oro/facial/dental pain
TRPA1 plays a prominent role in the oral-dental system which
is innervated by the trigeminus nerve. In a rodent model of
tooth injury, TRPA1 expression is increased and contributes to
hyperalgesia and allodynia [111]. Pain associated with stim-
ulation of a sensitive tooth involves mechanotransduction.
The majority of pulpal afferents express ASIC3 and TRPA1,
that represent novel targets for the treatment of dentin sensi-
tivity [116]. Odontoblasts form the outermost cellular layer of
the dental pulp act as sensory receptor cells. They highly
express TRPA1, which plays a key role in mediating noxious
cold responses in odontoblasts [83, 84].
Vital bleaching procedures are popular means of improving
the appearance of discolored teeth. These whitening products
contain peroxides which come in contact with the teeth. Many
users undergoing peroxide based whitening procedures com-
plain of bleaching sensitivity (BS) arising in the treated teeth.
TRPA1 is activated by the oxidizer compounds including
hydrogen peroxide and direct activation of intradental nerve
activity via TRPA1 [181]. Nerve Growth Factor (NGF) regu-
lates TRPA1 by increasing its functional activity in trigeminal
ganglion neurons by upregulation of its expression. This upre-
gulation of TRPA1 likely plays an important role in the devel-
opment of hyperalgesia following nerve injury and
inflammation in the orofacial region [71].
TRPA1 in cardiovascular diseases
Based on the remarkable activation of TRPA1 by garlic, it is
intriguing to speculate that this channel might be involved in
protective effects against cardiovascular diseases [263].
However, it has been shown that the ultimate cardiovascular
active compound derived from garlic is the gaseous mes-
senger H2S, which leads to vasorelaxation via KATP induced
hyperpolarization in smooth muscles, prevents leukocyte
adhesion, reduces cardiac arrhythmias, and acts cardiopro-
tective (a concise review in [166]).
The effect of TRPA1 activation might be explained by
changes in endothelial [Ca2+]i and dilation of pressurized
vessels with myogenic tone. This dilation is attenuated by
disruption of the endothelium and by blocking of TRPA1 with
HC-030031. The AITC-induced dilation is insensitive to NOS
or cyclooxygenase inhibition but requires K+ channels which
mediate cell hyperpolarization [80]. This mechanism might
also explain the benefical effect of TRPA1 activators on high
blood pressue. TRPA1 agonists significantly increase the blood
flow in skin. Also, a TRPA1-dependent relaxation is present in
mesenteric arteries. Intravenously-injected TRPA1 agonists
induce a transient hypotensive response accompanied by
decreased heart rate. These effects are not much influenced
by TRPV1, CGRP or substance P. The cholinergic antagonist,
atropine sulphate, inhibites the depressor response and slows
Pflugers Arch - Eur J Physiol (2012) 464:425–458
heart rate caused by TRPA1 activation. Thus, TRPA1-
mediated vasodilation influence changes in blood pressure
possibly via the autonomic system reflexes and may contribute
to the vasovagal/neurocardiogenic syncope disorders [230].
Diesel exhaust, which is emitted from on- and off-road
sources, triggers adverse cardiovascular effects like arrhyth-
mias. These arrhythmias are mediated by airway sensory
nerves expressing TRPA1. TRPA1 activation causes a
centrally-mediated autonomic imbalance and heightened
risk of arrhythmia. Exposures of rats to diesel exhausts
increase sympathetic tonus, prolong ventricular depolariza-
tion and shorten repolarization periods [115].
TRPA1 in GI tract diseases
In the esophagus, TRPA1 is present on esophageal sensory
afferents and plays an important role in esophageal nociception.
Both, PAR2 and TRPA1 are expressed in esophageal nodose
neurons. Esophageal mast cell activation induces long-lasting
mechanical hypersensitivity in vagal nodose C fibers. Mast cell
tryptase via PAR2-mediated pathways sensitizes sensory nerve
and induces hyperalgesia, which can be evoked by esophagus
distension. TRPA1 inhibitors strikingly reduce mechanical
hypersensitivity induced by either mast cell activation or
PAR2 agonists [314].
TRPA1 is expressed in primary sensory afferents inner-
vating the stomach, and is involved in visceral hypersensi-
tivity in rats. Gastric distention induced the activation of
extracellular signal-regulated protein kinase 1/2 (ERK1/2)
in DRG and nodose ganglia neurons, which express TRPA1.
Intrathecal injection of TRPA1 antisense RNAs attenuates
the visceromotor response, and suppresses ERK1/2 activa-
tion in DRG, but not NG. The TRPA1 inhibitor HC-030031
suppresses the response to noxious gastric distention, show-
ing that TRPA1 in primary afferents is a therapeutic target
for the reduction of visceral hypersensitivity [152].
In patients with irritable bowel syndrome (IBS), stressful
life events can have striking influences on visceral percep-
tion. TRPA1 is involved in the stress-induced visceral
hyperalgesia, which is probably due to an upregulation of
TRPA1 in the colonic afferent DRG. These neurons co-
express TRPA1 and TRPV1, both considered as targets to
treat the stress-induced visceral hyperalgesia [316].
Colitis is coupled to a neurogenic component involving
TRPA1. Intracolonic administration of MO or trinitroben-
zene sulfonic acid (TNBS) in mice leads to a severe colitis
that is maintained by upregulation of TRPA1 [144, 308].
TRPA1 is expressed in DRGs projecting to the colon. Itra-
colonic administration of TRPA1 agonists causes expression
of c-Fos in laminae I-II of the spinal dorsal horn at sacral
segment S1. This results in mild colonic inflammation [48].
Activation of colonic TRPA1 channels is signaled to the
spinal cord and mild colitis enhances this afferent input.
Pflugers Arch - Eur J Physiol (2012) 464:425–458
Noteworthy, neonatal colon injury results in a long-lasting
visceral hypersensitivity driven by an early increase in
growth factor expression and maintained by permanent
changes in TRPA1 function [56].
The neuropeptides CGRP and substance-P are released
from extrinsic sensory neurons, and play an important role
in experimental colitis [308]. In colitis models, TRPA1 acti-
vation causes an enhanced release of colonic substance-P and
CGRP. The inducer of inflammation TNBS binds covalently
to cysteine and lysine residues of TRPA1. Mice with TNBS-
colitis have increased colonic neuropeptide release mediated
by TRPA1. Endogenous products of inflammatory lipid per-
oxidation also induced TRPA1-dependent release of colonic
neuropeptides. Colitis induction is inhibited by TRPA1 block.
Activation and sensitization of TRPA1 and release of
substance-P induce and maintain colitis in mice [87].
Pancreatic inflammation is coupled to both channels in
pancreatic nodose ganglia and DRG sensory neurons (identi-
fied by content of retrograde tracer). During pancreatic inflam-
mation induced by caerulein, TRPA1 antagonists reduced
caerulein-induced pain and inflammation. TRPV1 and TRPA1
inhibitors have synergistic effects. Both channels determine the
excitability of pancreatic sensory neurons in vagal and spinal
pathways. Specific antagonists could be developed to reduce
pain in patients with acute pancreatitis [249].
TRPA1 in respiratory disease
The exposure of the upper respiratory tract to irritants alters
the normal mammalian exhalation pattern, decreasing the
respiration rate. This pattern of respiration rate depression
has been used as an indicator of sensory irritation, and
TRPA1 is at least partially responsible for this effect [245].
Activation of nasal trigeminal nerve endings by polluted air,
oxidative stress or chlorine induces respiratory depression,
nasal obstruction, sneezing, cough, and pain. Since TRPA1
is strongly activated by hypochlorite and hydrogen peroxide
in primary sensory neurons, it seemingly acts as an oxidant
detector in airway sensory neurons [30]. Chemosensory
airway reflexes can provoke severe complications in
patients affected by inflammatory airway conditions like
rhinitis and asthma.
Coughing is the probably the most frequent reason for
consultation with a physician. Endogenous inflammatory
mediators such as PGE2 and BK are elevated in respiratory
disease. TRPA1 expressed on respiratory vagal C fibres,
often in addition with TRPV1, is a main “effector” of
tussive responses to these agents. TRPA1 blockers inhibit
the tussive response to PGE2 and BK, and TRAP1 is prob-
ably one of the most promising targets for the development
of anti-tussive drugs [106]. However, TRPA1-mediated acti-
vation of cough can be modest compared to that mediated
by TRPV1, since stimulation of TRPA1 stimulation is less
447
efficient than that of TRPV1 to induce sustained activation
of airway C-fibers [41].
Asthma is an inflammatory disorder caused by airway
exposures to allergens and chemical irritants such as ciga-
rette smoke, chlorine, aldehydes, and scents. Endogenous
TRPA1 agonists, ROS, and lipid peroxidation products are
other potent drivers of allergen-induced airway inflamma-
tion in asthma. In the murine ovalbumin model, the down-
regulation of TRPA1 inhibits allergen-induced leukocyte
infiltration in the airways, reduces cytokine and mucus
production, and almost completely abolishes airway hyper-
reactivity to contractile stimuli. Since this pattern of effects
is also elicited by TRPA1 antagonists, TRPA1 may represent
a promising pharmacological target for the treatment of
asthma and other allergic inflammatory conditions. [44]. In
certain subjects, an early asthmatic response (EAR) is fol-
lowed by a late asthmatic response (LAR), but treatments
aimed at attenuating the EAR generally fail to affect LAR.
LAR evoked by allergen challenge is caused by triggering
airway sensory nerves via the activation of TRPA1. This
initiates a central reflex event, leading to a parasympathetic
cholinergic constrictor response [234].
TRPA1 is also implicated in the pathogenesis of chronic
obstructive pulmonary disease (COPD). Human lung fibro-
blasts and pulmonary alveolar epithelial cell express TRPA1,
and its activation promotes the release of the chemokine IL-8,
an effect attenuated by TRPA1 selective antagonists [196].
Thousands of persons experience accidental high-level
irritant exposures each year, but most recover and few die.
Persistent airway hyperresponsiveness after exposure to an
irritant, gas, vapor or fumes is the clinical hallmark of
asthma or reactive airways dysfunction syndrome (RADS)
[39]. Many chemicals present in these irritant agents activate
TRPA1 on these vagal sensory afferents and lead to central
reflexes, including also dyspnea and changes in breathing
pattern [26]. There are two types of cough reflexes. The
mechanosensory type via olfaction and larynx movements
in close proximity to the esophageal opening is mainly
mediated by A fibers. The second type, the chemosensory
type, has evolved to afford protection against respiratory
tract infections, or the inhalation of high levels of irritant
gases and particulates. This chemosensory type of reflex
heavily depends on TRPA1, that becomes activated or
hyperactivated after lung injury, with lung inflammation,
or in response to chemicals [38]. The chemosensory cough
reflex occurs via C-fibers, that cause a sensation of irritancy
and an itchy urge-to-cough that mimic the urge-to-cough
sensations associated with respiratory tract infection, post-
infection, gastroesophageal reflux disorders, and inflamma-
tory airway diseases [283]. Except for the action of exoge-
nous irritants, direct TRPA1 activation in sensory nerves
during cough can also occur via GPCR pathway (PGE2
and BK receptors) [178]. Blockage of TRPA1 represents a
448
novel therapy for the treatment of cough in humans [105,
277]. The inhalation of sulfureous vapors and thiols like
cysteine or cysteamine is traditionally used to improve air-
ways irritation [239]. It is tempting to speculate that these
compounds trap endogenous activators of TRPA1 present in
the inflammatory soup or, alternative, de-alkylate by sulfur
exchange alkylated forms of TRPA1, restoring the channel
in its native form, eventually soothing inflammation.
Finally, since TRPA1 activators are widespread in nature,
the possibility exists that the inhalation of pollen, especially
the one of asteraceous plants that contain highly electro-
philic exomethylene lactones, might activate TRPA1, trig-
gering inflammation and aggravating the discomfort
associated to the reaction to the allergenic proteins of pollen.
The gravity of symptoms associated to the allergy to astera-
ceous plant like Ambrosia artemisiifolia L. has been asso-
ciated to pollution of the urban environment with ozone or
acrolein, electrophilic compounds that act as TRPA1 activa-
tors [103]. On the other hand, the presence of high concen-
trations of electrophilic compounds in the pollen itself has
been demonstrated, suggesting that activation of TRPA1 by
small molecule electrophilic compounds naturally present in
the pollen could add injury to the allergenic offense trig-
gered by pollen proteins [268]. In this context, pollen might
represent a vector of non-volatile electrophilic compounds
to the airways. Several exomethylene-γ-lactones isolated
from common ragweed are potent traps of thiol groups and
activate TRPA1. Interestingly, these compounds can also
activate bitter receptors [37], a type of GPCR that are highly
expressed in human airway smooth muscles, potently caus-
ing relaxation [69].
TRPA1 in the urogenital system
A majority, but not all TRPA1 nerves show immunoreactivity
for CGRP or TRPV1. In the urothelium, TRPV1 is located to
the outer layers whereas TRPA1 is observed in basal urothelial
cells. Urodynamic parameters are changed after disruption of
the urothelial barrier with protamine sulfate. TRPA1, probably
together with TRPV1 [168, 218, 267], is activated by H2S and
participate to development of inflammatory bladder disease
[261]. Additionally, acrolein, which can be formed endoge-
nously under conditions of inflammation, aggravates this sit-
uation [190]. Intravesical TRPA1 activators also initiate
detrusor overactivity that has direct clinical implications.
In chronic pain disorders, such as irritable bowel syn-
drome, endometriosis, fibromyalgia syndrome and also cys-
titis, substance P and CGRP play a decisive role. Exogenous
and endogenous oxidative stress is involved in the patho-
genesis of interstitial cystitis/bladder pain syndrome and
other chronic pain conditions [97].
Spinal cord injury (SCI) results in tissue damage, inflam-
mation and changes in bladder contractility and in voiding
Pflugers Arch - Eur J Physiol (2012) 464:425–458
behavior. Alteration in bladder contractility following SCI is
accompanied by an enhanced activity of TRPA1. SCI
induced increase in the number of non-voiding contractions
(NVCs), an important parameter associated with the over-
active bladder (OAB) etiology, besides alterations in other
urodynamic parameters. The TRPA1 antagonist HC-030031
decreases the number and the amplitude of NVCs. Thus,
TRPA1 activation and up-regulation seem to exert an impor-
tant role in OAB following SCI [7].
In prostate hyperplasia patients, TRPA1 is also involved in
the bladder outlet obstruction (BOO). The induction of OAB
by BOO might result from TRPA1 in the bladder sensory
transduction via TRPA1 located in the bladder epithelium
[75]. However, these findings have to be confirmed.
Conclusion and future perspectives
TRPA1 is a chemosensory channel that constitutes both an
attractive drug target and a model channel for studying
structural and biophysical properties. The TRPA1 gating
mechanisms are still poorly understood. Although it is well
accepted that reactive compounds activate the channel via
covalent modification of nucleophilic sites in the N-
terminus, the chemical reactions are not well understood. It
is still unclear how channel activation is switched off, and
second, how and which biochemical processes control via-
bility of the channels for subsequent activation after inacti-
vation (desensitization). Additionally, some Michael
addition reactions are reversible but other covalent modifi-
cations are irreversible. We still do not completely under-
stand the role of Ca2+ and the interference with the cytosolic
Ca2+ concentrations of this highly Ca2+ permeable channel.
Another urgent problem concerns the quite dramatic differ-
ences between TRPA1 channels from different species [53].
The important species dependency often concerns bimodal
action of many TRPA1 modulators (e.g. menthol and caf-
feine). Since activation of TRPA1 can also occur via a more
classical lock-and-key activation, binding sites for these non-
electrophilic activators and their role as possible open pore
blockers need to be clarified. Obviously, a better understand-
ing of these mechanisms is critical for screening novel
TRPA1 modulators that might be used as possible therapeu-
tic agents. In this regard, it is also important to differentiate
between beneficial effects of TRPA1 block versus effects of
TRPA1 activation via slow depolarization and subsequent
inactivation of voltage dependent Na+ or Ca2+ channels.
A unique feature of TRPA1 is its huge potential for regu-
lation by dietary intake of channel modulators. Surprisingly,
we still do not know which concentrations of these com-
pounds are really reached in target organs and what are donw-
stream targets of such TRPA1 activation. Many covalent and
oxidant activators of TRPA1 also activate Nrf2, the master
regulator of antioxidative responses. This transcription factor
Pflugers Arch - Eur J Physiol (2012) 464:425–458
causes an increased expression of antioxidant enzymes, also
inhibiting inflammatory responses, and the two systems might
be somewhat related, with TRPA1 acting as a sensory alert for
oxidant and electrophilic insults, and Nrf2 representing
instead our defense line against these agents.
It is well established that TRPA1 mediates acute and
chronic pain and plays an important role in initiation but
also progression and maintenance of chronic inflammatory
diseases and tissue injuries, including asthma, diabetes,
arthritis and skin diseases. In addition to the many effects
of neuronal cells types, TRPA1 is an important channel also
in non-sensory tissues, such as epithelium, smooth muscle
cells, and fibroblasts. The function of TRPA1 in those cells
is still poorly understood. Given the widespread potential
targets for TRPA1 modulators, it is essential to understand
the genetics, biophysics and physiological role of this fasci-
nating TRPA1 channel.
Acknowldegments We thank the members of the Laboratory of Ion
Channel Research for helpful discussions. This work was supported by
grants from the Belgian Federal Government (IUAP P5/05), the
Research Foundation-Flanders (G.0172.03, G.0565.07 and
G.0149.03), and the Research Council of the KU Leuven (GOA
2004/07 and EF/95/010).
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