Structural insights into the molecular mechanism of mouse TRPA1 activation and inhibition

Samanta, Amrita; Kiselar, Janna; Pumroy, Ruth A.; Han, Seungil; Moiseenkova-Bell, Vera Y.

doi:10.1085/jgp.201711876

Cited by 26 publications

(28 citation statements)

References 51 publications

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“…Most TRP channels have a low open probability with voltage stimulation alone and require specific ligand interactions or other stimuli to fully open. Structural analysis of TRPV, TRPM, TRPA, and TRPML channels suggest that their VSD-like domains form ligand binding sites but the S4 remains relatively static during activation (41)(42)(43)(44)(45). For several TRP channel subtypes, the biophysical mechanism of current rectification is achieved through extrinsic mediators, like divalent cation block of TRPM7 (17,18).…”

Section: Gating Charge Transfer Is Required To Polymodally Activate Tmentioning

confidence: 99%

Opening TRPP2 ( PKD2L1 ) requires the transfer of gating charges

Vien

Yarov‐Yarovoy

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The opening of voltage-gated ion channels is initiated by transfer of gating charges that sense the electric field across the membrane. Although transient receptor potential ion channels (TRP) are members of this family, their opening is not intrinsically linked to membrane potential, and they are generally not considered voltage gated. Here we demonstrate that TRPP2, a member of the polycystin subfamily of TRP channels encoded by the PKD2L1 gene, is an exception to this rule. TRPP2 borrows a biophysical riff from canonical voltage-gated ion channels, using 2 gating charges found in its fourth transmembrane segment (S4) to control its conductive state. Rosetta structural prediction demonstrates that the S4 undergoes ∼3- to 5-Å transitional and lateral movements during depolarization, which are coupled to opening of the channel pore. Here both gating charges form state-dependent cation–π interactions within the voltage sensor domain (VSD) during membrane depolarization. Our data demonstrate that the transfer of a single gating charge per channel subunit is requisite for voltage, temperature, and osmotic swell polymodal gating of TRPP2. Taken together, we find that irrespective of stimuli, TRPP2 channel opening is dependent on activation of its VSDs.

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Section: Gating Charge Transfer Is Required To Polymodally Activate Tmentioning

confidence: 99%

Opening TRPP2 ( PKD2L1 ) requires the transfer of gating charges

Vien

Yarov‐Yarovoy

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, allicin can also activate TRPV1 through the same mechanism [70][71][72]. The non-electrophilic agonists include carvacrol, oleocanthal, Δ9-tetrahydrocannabinol (THC) and acidic pH, which activate TRPA1 by mechanisms not associated with cysteine modifications and which remain mostly unclarified [73][74][75].…”

Section: The Structures Of Thermotrp Channels Reveal Conformational Fmentioning

confidence: 99%

“…Nevertheless, recent studies have compared the structural rearrangements of TRPA1 in the presence of different agonists using techniques such as limited proteolysis combined with mass spectrometry [75]or circular dichroism spectroscopy only for the N-and C-terminal domains [79]. These robust methodologies show important interactions between cytoplasmatic domains involved in the gating of the channel [79], as well as differences between the activation with electrophilic and non-electrophilic agonists [75].…”

Section: The Structures Of Thermotrp Channels Reveal Conformational Fmentioning

confidence: 99%

TRP ion channels: Proteins with conformational flexibility

et al. 2019

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Ion channels display conformational changes in response to binding of their agonists and antagonists. The study of the relationships between the structure and the function of these proteins has witnessed considerable advances in the last two decades using a combination of techniques, which include electrophysiology, optical approaches (i.e. patch clamp fluorometry, incorporation of non-canonic amino acids, etc.), molecular biology (mutations in different regions of ion channels to determine their role in function) and those that have permitted the resolution of their structures in detail (X-ray crystallography and cryo-electron microscopy). The possibility of making correlations among structural components and functional traits in ion channels has allowed for more refined conclusions on how these proteins work at the molecular level. With the cloning and description of the family of Transient Receptor Potential (TRP) channels, our understanding of several sensory-related processes has also greatly moved forward. The response of these proteins to several agonists, their regulation by signaling pathways as well as by protein-protein and lipid-protein interactions and, in some cases, their biophysical characteristics have been studied thoroughly and, recently, with the resolution of their structures, the field has experienced a new boom. This review article focuses on the conformational changes in the pores, concentrating on some members of the TRP family of ion channels (TRPV and TRPA subfamilies) that result in changes in their single-channel conductances, a phenomenon that may lead to fine-tuning the electrical response to a given agonist in a cell.

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“…Another major difference is the lack of the so-called TRP-box, the sequence of the amino acids EWKFAR, which can be found in all TRP channels except TRPA1 [ 40 ]. TRPA1 is described to act as a chemo- or nociceptor [ 41 ]. The channel can be activated by pungent substances and plant ingredients like allicin from garlic, AITC from mustard oil, cinnamaldehyde from cinnamon oil, or gingerols from ginger [ 41 , 42 , 43 ].…”

Section: Trp Channels: General Structure and Functionmentioning

confidence: 99%

“…TRPA1 is described to act as a chemo- or nociceptor [ 41 ]. The channel can be activated by pungent substances and plant ingredients like allicin from garlic, AITC from mustard oil, cinnamaldehyde from cinnamon oil, or gingerols from ginger [ 41 , 42 , 43 ]. Expression of TRPA1 is often found in neuronal structures, building heterotetramers with TRPV1 [ 44 ].…”

Section: Trp Channels: General Structure and Functionmentioning

confidence: 99%

TRPs in Tox: Involvement of Transient Receptor Potential-Channels in Chemical-Induced Organ Toxicity—A Structured Review

Steinritz

Stenger

Dietrich

et al. 2018

Cells

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Chemicals can exhibit significant toxic properties. While for most compounds, unspecific cell damaging processes are assumed, a plethora of chemicals exhibit characteristic odors, suggesting a more specific interaction with the human body. During the last few years, G-protein-coupled receptors and especially chemosensory ion channels of the transient receptor potential family (TRP channels) were identified as defined targets for several chemicals. In some cases, TRP channels were suggested as being causal for toxicity. Therefore, these channels have moved into the spotlight of toxicological research. In this review, we screened available literature in PubMed that deals with the role of chemical-sensing TRP channels in specific organ systems. TRPA1, TRPM and TRPV channels were identified as essential chemosensors in the nervous system, the upper and lower airways, colon, pancreas, bladder, skin, the cardiovascular system, and the eyes. Regarding TRP channel subtypes, A1, M8, and V1 were found most frequently associated with toxicity. They are followed by V4, while other TRP channels (C1, C4, M5) are only less abundantly expressed in this context. Moreover, TRPA1, M8, V1 are co-expressed in most organs. This review summarizes organ-specific toxicological roles of TRP channels.

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Structural insights into the molecular mechanism of mouse TRPA1 activation and inhibition

Cited by 26 publications

References 51 publications

Opening TRPP2 ( PKD2L1 ) requires the transfer of gating charges

Opening TRPP2 ( PKD2L1 ) requires the transfer of gating charges

TRP ion channels: Proteins with conformational flexibility

TRPs in Tox: Involvement of Transient Receptor Potential-Channels in Chemical-Induced Organ Toxicity—A Structured Review

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