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J Gen Physiol. 2018 May 7;150(5):751-762. doi: 10.1085/jgp.201711876. Epub 2018 Apr 27.

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

Author information

1
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH.
2
Center for Proteomics, School of Medicine, Case Western Reserve University, Cleveland, OH.
3
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA.
4
Pfizer Inc., Groton, CT.
5
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH vmb@pennmedicine.upenn.edu.

Abstract

Pain, though serving the beneficial function of provoking a response to dangerous situations, is an unpleasant sensory and emotional experience. Transient receptor potential ankyrin 1 (TRPA1) is a member of the transient receptor potential (TRP) cation channel family and is localized in "nociceptors," where it plays a key role in the transduction of chemical, inflammatory, and neuropathic pain. TRPA1 is a Ca2+-permeable, nonselective cation channel that is activated by a large variety of structurally unrelated electrophilic and nonelectrophilic chemical compounds. Electrophilic ligands are able to activate TRPA1 channels by interacting with critical cysteine residues on the N terminus of the channels via covalent modification and/or disulfide bonds. Activation by electrophilic compounds is dependent on their thiol-reactive moieties, accounting for the structural diversity of the group. On the other hand, nonelectrophilic ligands do not interact with critical cysteines on the channel, so the structural diversity of this group is unexplained. Although near-atomic-resolution structures of TRPA1 were resolved recently by cryo-electron microscopy, in the presence of both agonists and antagonists, detailed mechanisms of channel activation and inhibition by these modulators could not be determined. Here, we investigate the effect of both electrophilic and nonelectrophilic ligands on TRPA1 channel conformational rearrangements with limited proteolysis and mass spectrometry. Collectively, our results reveal that channel modulation results in conformational rearrangements in the N-terminal ankyrin repeats, the pre-S1 helix, the TRP-like domain, and the linker regions of the channel.

PMID:
29703838
PMCID:
PMC5940248
DOI:
10.1085/jgp.201711876
[Indexed for MEDLINE]
Free PMC Article

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