An Unorthodox Mechanism Underlying Voltage Sensitivity of TRPV1 Ion Channel

While the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) channel is a polymodal nociceptor for heat, capsaicin, and protons, the channel's responses to each of these stimuli are profoundly regulated by membrane potential, damping or even prohibiting its response at negative voltages and amplifying its response at positive voltages. Therefore, voltage sensitivity of TRPV1 is anticipated to play an important role in shaping pain responses. How voltage regulates TRPV1 activation remains unknown. Here, it is shown that voltage sensitivity does not originate from the S4 segment like classic voltage‐gated ion channels; instead, outer pore acidic residues directly partake in voltage‐sensitive activation, with their negative charges collectively constituting the observed gating charges. Outer pore gating‐charge movement is titratable by extracellular pH and is allosterically coupled to channel activation, likely by influencing the upper gate in the ion selectivity filter. Elucidating this unorthodox voltage‐gating process provides a mechanistic foundation for understanding TRPV1 polymodal gating and opens the door to novel approaches regulating channel activity for pain management.