Abstract
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.
Highlights
Cytoplasmic milieu and external environment allowed the establishment of transchannel is a polymodal nociceptor for heat, capsaicin, and protons, the membrane ion concentration gradients, 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
Which in turn yielded a transmembrane electric potential. Such a membrane potential (Vm) has been widely utilized in cellular signaling:[2] voltage-gated ion channels alter Vm to elicit electrical signals for rapid communications;[3] voltage-sensitive it is shown that voltage sensitivity does not originate from the S4 segment like enzymes such as Ci–VSP couple changes 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
Our study suggested that voltage-sensing in Transient receptor potential vanilloid 1 (TRPV1) originates from conformational changes of the outer pore, where titratable acidic residues collectively contribute to the total charge movement
Summary
A fundamental parameter for voltage sensitivity is the total charge movement, q, which determines the steepness of voltage response.[5] TRPV1 is known to exhibit shallow voltage dependence.[11] By fitting a Boltzmann function to the G–V curve of mouse TRPV1 recorded in HEK293 cells (Figure 1c), the apparent q was estimated to be 0.72 ± 0.05 e0 (n = 4). Applying this approach to Kv channels yielded an apparent q of 5.3 e0.[17] it is well known that fitting the shape of G–V curves could. When the method was applied to BK channels, for which total gating charge could be directly measured from the gating current, an underestimation of 7.7% was seen.[25,26] the method we employed can reasonably estimate the gating charge
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