Research ArticleBiochemistry

Intracellular cavity of sensor domain controls allosteric gating of TRPA1 channel

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Science Signaling  23 Jan 2018:
Vol. 11, Issue 514, eaan8621
DOI: 10.1126/scisignal.aan8621

Regulatory cavity in TRPA1

The ion- and voltage-gated channel TRPA1 contributes to acute and chronic pain and itch, as well as vascular function. The channel is sensitive to temperature, pressure, various environmental irritants, and other molecules generated by injury or inflammation in an allosteric manner, meaning that the channel’s response to one stimulus alters its response to another. Zimova et al. investigated the structure of TRPA1 and found an intracellular region within the sensor domain that coordinates this complex allostery. For example, mutations in this cavity prevented stabilization of the channel by interacting intracellular phospholipids, resulting in dysregulated sensitivity to calcium ions. These findings suggest that alterations to the cavity may underlie chronic pain or itch in patients.


Transient receptor potential ankyrin 1 (TRPA1) is a temperature-sensitive ion channel activated by various pungent and irritant compounds that can produce pain in humans. Its activation involves an allosteric mechanism whereby electrophilic agonists evoke interactions within cytosolic domains and open the channel pore through an integrated nexus formed by intracellular membrane proximal regions that are densely packed beneath the lower segment of the S1–S4 sensor domain. Studies indicate that this part of the channel may contain residues that form a water-accessible cavity that undergoes changes in solvation during channel gating. We identified 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. This part of the sensor may also comprise a domain capable of binding to membrane phosphoinositides through which gating of the channel is regulated in a state-dependent manner.

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