Structural pharmacology of TRPA1 channel

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel predominantly expressed in sensory neurons. Genetic associations of TRPA1 with human diseases, along with extensive experimental evidence, have fueled interest in targeting TRPA1 for the treatment of pain, itch, and respiratory disorders. TRPA1 responds to a remarkably broad spectrum of agonists, including electrophilic and nonelectrophilic natural products, endogenous metabolites, marketed drugs, and synthetic compounds. Numerous antagonists have been identified, several of which have advanced into clinical trials. Recent cryogenic electron microscopy and mutagenesis studies have revealed at least ten distinct ligand-binding sites and modulation mechanisms. In this review, we highlight recent advances in the versatile pharmacology of TRPA1 and its therapeutic development, shaped by both natural and rationally designed modulators.