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

Neuron (2020-11-06)
Chang Liu, Rebecca Reese, Simon Vu, Lionel Rougé, Shannon D Shields, Satoko Kakiuchi-Kiyota, Huifen Chen, Kevin Johnson, Yu Patrick Shi, Tania Chernov-Rogan, Demi Maria Zabala Greiner, Pawan Bir Kohli, David Hackos, Bobby Brillantes, Christine Tam, Tianbo Li, Jianyong Wang, Brian Safina, Steve Magnuson, Matthew Volgraf, Jian Payandeh, Jie Zheng, Alexis Rohou, Jun Chen

The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.

Product Number
Product Description

Allyl isothiocyanate, contains BHT as stabilizer, 95%