A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel

Liu, Chang; Reese, Rebecca M.; Vu, Simon; Rougé, Lionel; Shields, Shannon D.; Kakiuchi-Kiyota, Satoko; Chen, Huifen; Johnson, Kevin M.; Shi, Yu; Chernov-Rogan, Tania; Greiner, Demi Maria Zabala; Kohli, Pawan Bir; Hackos, David H.; Brillantes, B.; Tam, Christine; Li, Tianbo; Wang, Jianyong; Safina, Brian S.; Magnuson, Steve; Volgraf, Matthew; Payandeh, Jian; Zheng, Jie; Rohou, Alexis; Chen, Jun

doi:10.1016/j.neuron.2020.10.014

Cited by 58 publications

(66 citation statements)

References 64 publications

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“…5), consistent with the observation that a non-covalent ligand binding confers a biased agonism of TRPA1 channels (Liu et al, 2020). The non-covalent binding agonist DNFB that activates TRPA1 without causing the channel desensitization is widely used for the model establishment of persistent dermatitis (Kaplan et al, 2012), which is unlike agonist AITC that covalently binds to and induces TRPA1 channel desensitization (Dai et al, 2007;Liu et al, 2020). Other non-covalent TRPA1 agonists such as peptide scorpion toxin (WaTx) or small molecule GNE551 can activate TRPA1 in a slow kinetics fashion without inducing channel desensitization and cause persistent pain (Lin King et al, 2019;Liu et al, 2020).…”

Section: Discussionsupporting

confidence: 85%

“…Chemical DNFB as an electrophilic reagent binds to TRPA1 through non-covalent hydrogen bonds with C621 and Y658 residues and a unique halogen bond between the fluorine of DNFB and Y684 residue (Fig. 5), consistent with the observation that a non-covalent ligand binding confers a biased agonism of TRPA1 channels (Liu et al, 2020). The non-covalent binding agonist DNFB that activates TRPA1 without causing the channel desensitization is widely used for the model establishment of persistent dermatitis (Kaplan et al, 2012), which is unlike agonist AITC that covalently binds to and induces TRPA1 channel desensitization (Dai et al, 2007;Liu et al, 2020).…”

Section: Discussionsupporting

confidence: 73%

“…The non-covalent binding agonist DNFB that activates TRPA1 without causing the channel desensitization is widely used for the model establishment of persistent dermatitis (Kaplan et al, 2012), which is unlike agonist AITC that covalently binds to and induces TRPA1 channel desensitization (Dai et al, 2007;Liu et al, 2020). Other non-covalent TRPA1 agonists such as peptide scorpion toxin (WaTx) or small molecule GNE551 can activate TRPA1 in a slow kinetics fashion without inducing channel desensitization and cause persistent pain (Lin King et al, 2019;Liu et al, 2020). Non-covalent agents are non-reactive to cytosolic abundant nucleophiles (such as glutathione) and are expected to sustain their concentration for longer time, thus leading to more persistent activation of TRPA1 (Liu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

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Selective activation of TRPA1 ion channel by skin sensitizer nitrobenzene DNFB

Sun

et al. 2021

Preprint

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BACKGROUND AND PURPOSE: Chemical 2, 4-dinitrofluorobenzene (DNFB), commonly called as Sanger’s reagent, is well known as skin sensitizer to cause dermatitis. However, how the DNFB causes skin inflammation remains unknown. In this study we aimed at identifying the molecular target that DNFB acts on. EXPERIMENTAL APPROACH: We used a fluorescent calcium imaging plate reader as an initial screening assay and patch-clamp recordings for validation. Molecular docking in combination with site-directed mutagenesis was carried out to investigate DNFB binding sites in TRPA1 ion channel. KEY RESULTS: We found the chemical DNFB that selectively activates TRPA1 channel with EC50 of 2.36 ± 0.26 µM. Single-channel recording reveals that DNFB increases the channel open probability and acts on three residues C621, Y658 and E625 critical for DNFB-mediated TRPA1 activation. CONCLUSION AND IMPLICATIONS: Our findings not only explain a molecular mechanism underlying the dermatitis and pruritus caused by chemical DNFB, but also provides a molecular tool that is 7.5-time more potent than current AITC molecule and can be used for elucidating TRPA1 channel pharmacology and pathology.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Selective activation of TRPA1 ion channel by skin sensitizer nitrobenzene DNFB

Sun

et al. 2021

Preprint

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“…The binding sites of TAS2Rs are buried in the transmembrane portion of the bitter taste receptors 17 , and the activation of TRPA1 by OC does not depend on canonical binding to intracellular cysteine residues 13 , rather OC activation of TRPA1 may involve lysine residues 18 or noncanonical binding in the transmembrane portion of TRPA1 19 .…”

Section: Discussionmentioning

confidence: 99%

Protein Suppresses Both Bitterness and Oleocanthal-elicited Pungency of Extra Virgin Olive Oil

Gachons

O’Keefe

Slade³

et al. 2021

Preprint

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The Mediterranean diet, considered one of the healthiest in the world, is characterized in part by the major source of its fat, which is extra virgin olive oil (EVOO). Among the health benefits of consuming EVOOs is the presence of phenolic compounds, which have been shown to lower the incidence of coronary heart disease and are suspected of providing many other health benefits. These phenolic compounds also contribute to the flavor of EVOO, adding both pungent and bitter notes that are valued by connoisseurs but reported to be unpleasant by naïve consumers. Here, we demonstrate that some food-derived proteins, when added to pungent and bitter EVOOs, reduce or even eliminate both the pungency and bitterness. This sensory loss seems to be caused by the proteins binding the pungent phenolic compound, oleocanthal, as well as bitter tasting phenolics, leaving them unable to activate their respective sensory receptors (TRPA1 and TAS2Rs). Thus, when used in various foods recipes (e.g. mayonnaise), pungent and bitter EVOOs may lose their pungent and bitter characteristics thereby rendering them more palatable to many consumers. These data also raise the question of whether the bioactivities of EVOO phenolics remain unchanged when consumed with and without protein-containing foods.

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“…Remarkably, this mechanism of action was distinct in that WaTx is a non-covalent gating modifier that does not directly promote the TRPA1 open state but instead stabilizes it. In contrast, another non-electrophilic compound, GNE551, was found to bind a hydrophobic transmembrane binding site (residue Q940) of TRPA1 to increase the channel’s open state without affecting Ca 2+ permeability [ 64 ]. Considering that most non-electrophilic TRPA1 agents have generally been regarded as non-selective compounds with low potency and efficacy [ 38 , 43 ], the continued discovery and development of highly selective non-covalent compounds present novel strategies for deciphering the properties and physiological significance of non-covalent TRPA1 activation.…”

Section: Pharmacology Of Trpa1 Channelsmentioning

confidence: 99%

Transient Receptor Potential Channel Ankyrin 1: A Unique Regulator of Vascular Function

Alvarado

Thakore

Earley

2021

Cells

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TRPA1 (transient receptor potential ankyrin 1), the lone member of the mammalian ankyrin TRP subfamily, is a Ca2+-permeable, non-selective cation channel. TRPA1 channels are localized to the plasma membranes of various cells types, including sensory neurons and vascular endothelial cells. The channel is endogenously activated by byproducts of reactive oxygen species, such as 4-hydroxy-2-noneal, as well as aromatic, dietary molecules including allyl isothiocyanate, a derivative of mustard oil. Several studies have implicated TRPA1 as a regulator of vascular tone that acts through distinct mechanisms. First, TRPA1 on adventitial sensory nerve fibers mediates neurogenic vasodilation by stimulating the release of the vasodilator, calcitonin gene-related peptide. Second, TRPA1 is expressed in the endothelium of the cerebral vasculature, but not in other vascular beds, and its activation results in localized Ca2+ signals that drive endothelium-dependent vasodilation. Finally, TRPA1 is functionally present on brain capillary endothelial cells, where its activation orchestrates a unique biphasic propagation mechanism that dilates upstream arterioles. This response is vital for neurovascular coupling and functional hyperemia in the brain. This review provides a brief overview of the biophysical and pharmacological properties of TRPA1 and discusses the importance of the channel in vascular control and pathophysiology.

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A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel

Cited by 58 publications

References 64 publications

Selective activation of TRPA1 ion channel by skin sensitizer nitrobenzene DNFB

Selective activation of TRPA1 ion channel by skin sensitizer nitrobenzene DNFB

Protein Suppresses Both Bitterness and Oleocanthal-elicited Pungency of Extra Virgin Olive Oil

Transient Receptor Potential Channel Ankyrin 1: A Unique Regulator of Vascular Function

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