Mechanisms governing irritant-evoked activation and calcium modulation of TRPA1

The TRPA1 ion channel is a chemosensory receptor that is critical for detecting noxious chemical agents that elicit or exacerbate pain or itch. Here we use structural and electrophysiological methods to elucidate how a broad class of reactive electrophilic irritants activate TRPA1 through a two-step cysteine modification mechanism that promotes local conformational changes leading to widening of the selectivity filter to enhance calcium permeability and opening of a cytoplasmic gate. We also identify a calcium binding pocket that is remarkably conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization, and activation by metabotropic receptors. These findings provide a structural basis for understanding how endogenous or exogenous chemical agents activate a broad-spectrum irritant receptor directly or indirectly through a cytoplasmic second messenger.