The lipoelectric mechanism and binding sites for other compounds. (A) Schematic illustration of the PUFA effect on the Shaker channel: negatively charged PUFAs shift the voltage dependence of a Kv channel in a negative direction along the voltage axis. (B) A PUFA binds with its hydrophobic acyl tail in the hydrophobic lipid bilayer or a hydrophobic pocket in the channel. From this position, the negatively charged carboxyl group of the PUFA electrostatically attracts the positively charged voltage sensor to open the intracellular gate of the ion channel. (C) Side view of the Kv1.2/2.1 chimera with Shaker side chains. Back and front domains are removed for clarity. Note that the VSDs and pore domains shown are from different subunits. Residues critical for quaternary ammonium compounds (Zhou et al., 2001) (I470 and V474 in green), pore-blocking toxins (MacKinnon et al., 1990) (D431, T449, and V451 in magenta), voltage sensor–trapping toxins (Swartz and MacKinnon, 1997) (L327, A328, and V331 in red), and retigabine (Lange et al., 2009) (I400, G406, V407, M440, and A464 in yellow) are shown as sticks. The gating charges R362, R365, R368, and R371 are marked as blue sticks. Residue numbering refers to Shaker.