Abstract
Transient receptor potential (TRP) channels have been extensively studied over the past years. Yet, in most cases, the gating mechanisms of these polymodal cation channels still remain a puzzle. Using the nociceptive channel TRPA1 as an example, we discuss the role of dynamic regulation of the pore size (pore dilatation) on channel gating. Additionally, we critically revise current knowledge of the role of intracellular domains, such as ankyrin repeats and EF hand motifs, in channel activation and function. Finally, we assess some problems inherent to activation of TRPA1 by the reaction of electrophilic compounds with the nucleophilic thiol sink of N-terminal reactive cysteines.