Possible interpretations of differential effects on different steps. (A) Three possible models for the S4 movement during the opening step. (B) The new PUFA action site compared with previously described sites. The Shaker channel is viewed from the extracellular side. The color coding follows that from Fig. 1 C. Green denote residues critical for the binding of quaternary ammonium compounds, magenta is for pore-blocking toxins, red is for voltage sensor–trapping toxins, yellow is for retigabine, and orange is for PUFA in the present investigation. The gating charges R362, R365, R368, and R371 are marked as blue sticks.