Transient receptor potential A1 channel in nociceptive sensation of weak acids and carbon dioxide and its regulation

Pain sensation is critical to animal survival as it serves as an early warning system. Noxious stimuli are detected by the primary sensory neurons (nociceptors) whose cell bodies reside in the trigeminal and dorsal root ganglia. In order to better understand the sensory transduction pathway, the primary step would be to identify the specific molecular sensor for specific pain-evoking stimuli and uncover its gating mechanism. One nociceptive sensor is the transient receptor potential A1 (TRPA1) channel, which is the principle detector for a variety of environmental irritants and pungent compounds, such as mustard oil and cinnamladehyde. Responses of TRPA1 to pungent compounds are further regulated by extracellular Ca2+. However, the underlying mechanism is not clearly understood. Here we identified a TRPA1 pore mutant that has greatly reduced Ca2+ permeability. By studying the function of this mutant, we have discovered that the Ca2+ regulatory effect requires Ca2+ entry into the cell and the resulting increase of its intracellular concentration.;High concentrations of CO2, as in carbonated beverages, are known to cause pungent or painful sensation which is thought to originate with the activation of trigeminal nociceptors that innervate the nasal and oral cavity. The molecular targets remain however obscure. Here we showed that TRPA1 is both necessary and sufficient to mediate trigeminal responses to CO2. CO2 causes both extracellular and intracellular acidification and we identified the proximate stimulus that gates TRPA1 in response to CO2 is intracellular protons. Weak organic acids, such as acetic acid in vinegar, are also irritation or pain-evoking stimuli and they can acidify the cell cytosol. Similar to CO2, We demonstrated that the molecular sensor for various weak acids in the trigeminal system is TRPA1, and it does so by sensing intracellular acidification. Our findings suggest a role of TRPA1 as a potential therapeutic target to relieve acidotic pain.