Allosteric model of activation of TRPV1 channels by voltage and capsaicin. (A) The model considers the action of the voltage sensor that can be in a resting (R_V) or activated state (A_V), and the ligand sensor that can be in the unbound (U) or bound state. The voltage sensor has an equilibrium constant J, the ligand sensor is characterized by the equilibrium constant Q, and the ionic pore by the equilibrium constant L. In addition, the model assumes that the voltage sensor is coupled to the pore by the allosteric constant D, the ligand sensor is coupled to the pore by the allosteric constant P, and that both sensors are coupled by the allosteric constant E. Because we performed all our studies at room temperature (22°C), we assumed that the temperature sensor would have a negligible contribution, remaining in its resting state. (B) In the absence of agonist, channel gating is driven by the activation of the voltage sensor; at saturating concentration of capsaicin (C), channel gating is largely voltage independent.