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The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryo- microscopy to determine the structure of full-length human TRPA1 to ∼4 Å resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents. The high-resolution electron cryo-microscopy structure of the full-length human TRPA1 ion channel is presented; the structure reveals a unique ankyrin repeat domain arrangement, a tetrameric coiled-coil in the centre of the channel that acts as a binding site for inositol hexakisphosphate, an outer poor domain with two pore helices, and a new drug binding site, findings that collectively provide mechanistic insight into TRPA1 regulation. Structure of multifunctional TRPA1 receptor TRP (transient receptor potential) channels are expressed by all eukaryotic organisms and act as sensors for a wide range of physical and chemical stimuli. This paper reports the high-resolution electron cryomicroscopy structure of full-length human TRPA1, a sensory receptor for noxious chemical agents such as wasabi. The overall structure of this membrane protein differs markedly from the previously published structure of TRPV1, as TRPA1 has many ankyrin repeat domains, a tetrameric coiled-coil in the center of the channel that appears to serve as a binding site for inositol hexakisphosphate and an outer pore domain with two pore helices. TRPA1 is associated with persistent pain, respiratory and chronic itch syndromes, so TRPA1 antagonists are of interest as potential analgesics.

The Transient Receptor Potential Ankyrin 1 channel (TRPA1), is a member of the large TRP family of ion channels, and functions as a Ca 2+ permeable non-selective cation channel in many different cell processes, ranging from sensory to homeostatic tasks. TRPA1 is highly conserved 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.

The myelin sheaths wrapped around axons by oligodendrocytes are crucial for brain function. In ischaemia myelin is damaged in a Ca(2+)-dependent manner, abolishing action potential propagation. This has been attributed to glutamate release activating Ca(2+)-permeable N-methyl-D-aspartate (NMDA) receptors. Surprisingly, we now show that NMDA does not raise the intracellular Ca(2+) concentration ([Ca(2+)]i) in mature oligodendrocytes and that, although ischaemia evokes a glutamate-triggered membrane current, this is generated by a rise of extracellular [K(+)] and decrease of membrane K(+) conductance. Nevertheless, ischaemia raises oligodendrocyte [Ca(2+)]i, [Mg(2+)]i and [H(+)]i, and buffering intracellular pH reduces the [Ca(2+)]i and [Mg(2+)]i increases, showing that these are evoked by the rise of [H(+)]i. The H(+)-gated [Ca(2+)]i elevation is mediated by channels with characteristics of TRPA1, being inhibited by ruthenium red, isopentenyl pyrophosphate, HC-030031, A967079 or TRPA1 knockout. TRPA1 block reduces myelin damage in ischaemia. These data suggest that TRPA1-containing ion channels could be a therapeutic target in white matter ischaemia.

Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that affects people of all ages. It is characterized by chronic eczema, constant pruritus, and severe discomfort. AD often progresses from mild annoyance to intractable pruritic inflammatory lesions associated with exacerbated skin sensitivity. The T helper-2 (Th2) response is mainly linked to the acute and subacute phase, whereas Th1 response has been associated in addition with the chronic phase. IL-17, IL-22, TSLP, and IL-31 also play a role in AD. Transient receptor potential (TRP) cation channels play a significant role in neuroinflammation, itch and pain, indicating neuroimmune circuits in AD. However, the Th2-driven cutaneous sensitization of TRP channels is underappreciated. Emerging findings suggest that critical Th2-related cytokines cause potentiation of TRP channels, thereby exaggerating inflammation and itch sensation. Evidence involves the following: (i) IL-13 enhances TRPV1 and TRPA1 transcription levels; (ii) IL-31 sensitizes TRPV1 via transcriptional and channel modulation, and indirectly modulates TRPV3 in keratinocytes; (iii) The Th2-cytokine TSLP increases TRPA1 synthesis in sensory neurons. These changes could be further enhanced by other Th2 cytokines, including IL-4, IL-25, and IL-33, which are inducers for IL-13, IL-31, or TSLP in skin. Taken together, this review highlights that Th2 cytokines potentiate TRP channels through diverse mechanisms under different inflammatory and pruritic conditions, and link this effect to distinct signaling cascades in AD. This review strengthens the notion that interrupting Th2-driven modulation of TRP channels will inhibit transition from acute to chronic AD, thereby aiding the development of effective therapeutics and treatment optimization.

Key Points The role of transient receptor potential (TRP) channels is best understood in the pain area. As TRP channels are expressed on peripheral nociceptors, where pain is generated, it is hoped that TRP channel blockers will be devoid of the side effects that limit the use of analgesic agents that act on the central nervous system. Several TRP cation channel subfamily V, member 1 (TRPV1) antagonists have advanced to clinical trials, but their side effects (which include hyperthermia and impaired noxious heat detection) have prevented any compounds from progressing beyond Phase II clinical trials. TRPV3 antagonists have shown efficacy in models of neuropathic and inflammatory pain, and one antagonist has entered Phase I clinical trials. An autosomal dominant mutation in the gene that encodes TRP cation channel subfamily A, member 1 (TRPA1) causes familial episodic pain syndrome. Indeed, TRPA1 antagonists have been shown to reduce cold hypersensitivity in rodent models of neuropathic pain without altering normal cold sensation in naive animals. Several TRP channels (such as TRPV1, TRPV4 and TRP cation channel subfamily M, member 8 (TRPM8)) are expressed in the urinary bladder, where they presumably function as sensors of stretch and chemical irritation. TRPV1 and TRPV4 antagonists improve bladder function in rodent models of cystitis. Populations of non-neuronal cells within the skin express many different types of TRP channels that are implicated in the regulation of several key cutaneous functions including skin-derived pruritus, proliferation, differentiation and inflammatory processes. TRPA1 and TRPV1 serve as polymodal sensors in the mammalian respiratory tract that integrate varied inflammatory, oxidant and hazardous irritant stimuli to produce noxious sensations (for example, breathlessness, the urge to cough and nasopharyngeal pain) and respiratory reflexes such as coughing. Several TRP channels — including members of TRP cation channel subfamily C (TRPC) and TRPV — influence the process of gas exchange by regulating airflow, blood flow and airway permeability. Mutations in at least six of the 28 members of the TRP channel superfamily are associated with heritable genetic diseases in humans. These mutations have implicated TRP channels in many pathophysiological states and expanded our understanding of the physiological role of these channels. The role of TRP channels in the brain remains to be elucidated, but it seems to be clear that some members of the superfamily are involved in neuronal excitability and neurotransmitter release. Genetic deletion of TRPC5 leads to an anxiolytic phenotype, whereas a point mutation in TRPC3 leads to ataxia. TRP channels also serve important functions in other diseases that are not fully explored in this Review. For example, cancer and metabolic diseases will be particularly interesting to watch in the future. Transient receptor potential (TRP) channels are a diverse family of cation channels. Here, the authors discuss recent developments in this area, highlight recent developments and setbacks in the field of pain research and analyse TRP channels as targets for skin, pulmonary and urological disorders. Transient receptor potential (TRP) cation channels have been among the most aggressively pursued drug targets over the past few years. Although the initial focus of research was on TRP channels that are expressed by nociceptors, there has been an upsurge in the amount of research that implicates TRP channels in other areas of physiology and pathophysiology, including the skin, bladder and pulmonary systems. In addition, mutations in genes encoding TRP channels are the cause of several inherited diseases that affect a variety of systems including the renal, skeletal and nervous system. This Review focuses on recent developments in the TRP channel-related field, and highlights potential opportunities for therapeutic intervention.

Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 alpha,beta-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify alpha,beta-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway neurogenic inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.

The redox-sensitive TRP channel TRPA1 is activated in hyperoxic and hypoxic conditions directly through modification of cysteine residues by O 2 and indirectly through prolyl hydroxylation by PHDs, enzymes related to the hypoxia-inducible factor HIF-1, thus helping to explain how O 2 is sensed by sensory and vagal neurons. Oxygen (O 2 ) is a prerequisite for cellular respiration in aerobic organisms but also elicits toxicity. To understand how animals cope with the ambivalent physiological nature of O 2 , it is critical to elucidate the molecular mechanisms responsible for O 2 sensing. Here our systematic evaluation of transient receptor potential (TRP) cation channels using reactive disulfides with different redox potentials reveals the capability of TRPA1 to sense O 2 . O 2 sensing is based upon disparate processes: whereas prolyl hydroxylases (PHDs) exert O 2 -dependent inhibition on TRPA1 activity in normoxia, direct O 2 action overrides the inhibition via the prominent sensitivity of TRPA1 to cysteine-mediated oxidation in hyperoxia. Unexpectedly, TRPA1 is activated through relief from the same PHD-mediated inhibition in hypoxia. In mice, disruption of the Trpa1 gene abolishes hyperoxia- and hypoxia-induced cationic currents in vagal and sensory neurons and thereby impedes enhancement of in vivo vagal discharges induced by hyperoxia and hypoxia. The results suggest a new O 2 -sensing mechanism mediated by TRPA1.

Background Transient receptor potential (TRP) ion channels play crucial roles in mediating responses to environmental stimuli, as well as regulating homeostasis and developmental processes in insects. Several members of the TRP superfamily are potential molecular targets for insecticides or repellents, indicating their research value in pest control. This study focuses on Spodoptera frugiperda, an important invasive pest in China known for its wide host range and strong reproductive capacity. Currently, there is a lack of molecular research on the TRP channels of the invasive pest S. frugiperda . Results In this study, we identified 15 TRP family genes in S. frugiperda , which were classified into six subfamilies. The TRPP subfamily gene was not identified, whereas the TRPA subfamily contained the highest number of members in this insect. Real-time quantitative polymerase chain reaction (RT-qPCR) experiments revealed widespread expression of TRP channel genes across various developmental stages of S. frugiperda . However, TRPM and TRPML were highly expressed only in eggs. Transcripts of TRP channel genes were detected in the sensory organs of mature adults, including the mouthparts, antennae, compound eyes, legs, wings, harpagones, and ovipositors, as well as in tissues of 5th instar larvae (hemocytes, central nervous system, midgut, fat body, and Malpighian tubules). To explore the potential role of TRP channels in immunity, we detected their levels in larvae 24 h after infection with Serratia marcescens . The expression levels of TRPML , TRPL , and the Pain genes were significantly up-regulated, suggesting their important roles in immune responses to S. marcescens . Conclusions The results of this study extend our knowledge of these critical sensory channels in S. frugiperda. This knowledge provides a basis for the future development of insecticides that target these channels, thereby promoting the safe and effective control of this key pest.

Phosphatidylinositol 4,5-bisphosphate (PIP₂) plays a central role in the activation of several transient receptor potential (TRP) channels. The role of PIP₂ on temperature gating of thermoTRP channels has not been explored in detail, and the process of temperature activation is largely unexplained. In this work, we have exchanged different segments of the C-terminal region between cold-sensitive (TRPM8) and heat-sensitive (TRPV1) channels, trying to understand the role of the segment in PIP₂ and temperature activation. A chimera in which the proximal part of the C-terminal of TRPV1 replaces an equivalent section of TRPM8 C-terminal is activated by PIP₂ and confers the phenotype of heat activation. PIP₂, but not temperature sensitivity, disappears when positively charged residues contained in the exchanged region are neutralized. Shortening the exchanged segment to a length of 11 aa produces voltage-dependent and temperature-insensitive channels. Our findings suggest the existence of different activation domains for temperature, PIP₂, and voltage. We provide an interpretation for channel-PIP₂ interaction using a full-atom molecular model of TRPV1 and PIP₂ docking analysis.

Zinc is an essential biological trace element. It is required for the structure or function of over 300 proteins, and it is increasingly recognized for its role in cell signaling. However, high concentrations of zinc have cytotoxic effects, and overexposure to zinc can cause pain and inflammation through unknown mechanisms. Here we show that zinc excites nociceptive somatosensory neurons and causes nociception in mice through TRPA1, a cation channel previously shown to mediate the pungency of wasabi and cinnamon through cysteine modification. 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. These findings identify TRPA1 as an important target for the sensory effects of zinc and support an emerging role for zinc as a signaling molecule that can modulate sensory transmission.