The study by Hinman et al. investigates the activation of the TRPA1 ion channel by reversible covalent modification. TRPA1, activated by pungent compounds like allyl isothiocyanate (AITC), is a key receptor for pain and inflammation. The authors show that TRPA1 activation by these compounds is due to their electrophilic nature, which forms covalent adducts with cysteine residues within the cytoplasmic N-terminal domain of the channel. This mechanism is distinct from classical lock-and-key binding and involves irreversible modification. The study also demonstrates that TRPA1 mutants insensitive to electrophilic agonists retain their ability to function as receptor-operated channels, indicating that distinct biochemical pathways contribute to TRPA1 activation. The findings provide a mechanistic framework for understanding the activation of TRPA1 by various environmental and endogenous stimuli.The study by Hinman et al. investigates the activation of the TRPA1 ion channel by reversible covalent modification. TRPA1, activated by pungent compounds like allyl isothiocyanate (AITC), is a key receptor for pain and inflammation. The authors show that TRPA1 activation by these compounds is due to their electrophilic nature, which forms covalent adducts with cysteine residues within the cytoplasmic N-terminal domain of the channel. This mechanism is distinct from classical lock-and-key binding and involves irreversible modification. The study also demonstrates that TRPA1 mutants insensitive to electrophilic agonists retain their ability to function as receptor-operated channels, indicating that distinct biochemical pathways contribute to TRPA1 activation. The findings provide a mechanistic framework for understanding the activation of TRPA1 by various environmental and endogenous stimuli.