Irritant-evoked activation and calcium modulation of the TRPA1 receptor

@article{Zhao2020IrritantevokedAA,
  title={Irritant-evoked activation and calcium modulation of the TRPA1 receptor},
  author={Jianhua Zhao and John V. Lin King and Candice E. Paulsen and Yifan Cheng and David Julius},
  journal={Nature},
  year={2020},
  volume={585},
  pages={141 - 145}
}
The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids 1 . TRPA1 is also a ‘receptor-operated’ channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch, making it an attractive target for novel analgesic therapies 2 . However, the… 
Functional evidence of distinct electrophile-induced activation states of the ion channel TRPA1
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The authors' simulations reveal that an open pore is structurally stable in the presence of open ‘pockets’ in the C621 / C665 region, but rapidly collapses and closes when these pockets are shut, while molecules bound at C665 are shown to be able to rotate in and out of the pocket, allowing for immediate stabilisation of transient open states.
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The therapeutic potential of the TRPA1 channel is highlighted, which is expected to become a novel direction for the prevention and treatment of health conditions such as cancer and neurodegenerative diseases.
Transient receptor potential ankyrin 1 channel: An evolutionarily tuned thermosensor.
TLDR
This review aims at providing some of the recent knowledge on the molecular mechanisms underlying the temperature sensitivity of TRPA1, and demonstrates how the search for differences in temperature and chemical sensitivity between human and mouse TRPA 1 orthologues can be a useful approach to identifying important domains with a key role in channel activation.
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TLDR
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Phospho-Mimetic Mutation at Ser602 Inactivates Human TRPA1 Channel
TLDR
Using mutagenesis, electrophysiology, and molecular simulations, it is found that the possible structural impact of a modification (mutation or phosphorylation) of Ser602 represents an important regulatory site through which the intracellular signaling cascades may act to reversibly restrict or “dampen” the conformational space of the TRPA1 channel and promote its transitions to the closed state.
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References

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Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines
The nervous system senses peripheral damage through nociceptive neurons that transmit a pain signal. TRPA1 is a member of the Transient Receptor Potential (TRP) family of ion channels and is
The Nociceptor Ion Channel TRPA1 Is Potentiated and Inactivated by Permeating Calcium Ions*
TLDR
Evidence is provided that the effect of extracellular Ca2+ on these processes is indirect and can be entirely attributed to entry through TRPA1 and subsequent elevation of intracellular calcium, and that potentiation and inactivation are independent processes.
Structure of the TRPA1 ion channel suggests regulatory mechanisms
TLDR
Single-particle electron cryo- microscopy is used to determine the structure of full-length human TRPA1 to ∼4 Å resolution and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.
Intracellular cavity of sensor domain controls allosteric gating of TRPA1 channel
TLDR
Findings suggest that alterations to the cavity may underlie chronic pain or itch in patients, and identify conserved polar residues facing the putative lower crevice of the sensor domain that were crucial determinants of the electrophilic, voltage, and calcium sensitivity of the TRPA1 channel.
TRPV1 structures in distinct conformations reveal mechanisms of activation
TLDR
Pharmacological probes are exploited to determine structures of two activated states of the capsaicin receptor, TRPV1, and allosteric coupling between upper and lower gates may account for rich physiological modulation exhibited by TRpV1 and other TRP channels.
Structural Insights into Electrophile Irritant Sensing by the Human TRPA1 Channel.
TLDR
The structural and functional studies provide the molecular basis for electrophile recognition by the extraordinarily reactive C621 in TRPA1 and mechanistic insights into electrophiles-dependent conformational changes in TRpa1, and provides a platform for future drug development targeting TRPA2.
Mammalian transient receptor potential TRPA1 channels: from structure to disease.
TLDR
The current knowledge about the mammalian TRPA1 channel is reviewed, linking its unique structure, widely tuned sensory properties and complex regulation to its roles in multiple pathophysiological conditions.
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