R 1 in the Shaker S 4 occupies the gating charge transfer center in the resting state Meng -

In the voltage-gated Shaker K channel, the probability of opening increases from 10 to nearly 1 over a range of <100 mV (Islas and Sigworth, 1999). This exquisite sensitivity to voltage is conferred by positively charged amino acid residues located in the S4 transmembrane segment. In response to membrane depolarization, the side chains of four S4 arginine residues (R1–R4) in each of the four channel subunits are transferred some or all of the way across the transmembrane electric field (Fig. 1 A) (Aggarwal and MacKinnon, 1996; Seoh et al., 1996). These conformational changes convert the voltage sensor domain from its resting state, in which S4 adopts its most inward position, to its fully activated state, in the process transferring 13 e0 across the transmembrane electric field (Schoppa et al., 1992; Aggarwal and MacKinnon, 1996; Seoh et al., 1996; Islas and Sigworth, 1999). How the charged residues cross the transmembrane field is not well understood. Recently, Tao et al. (2010) proposed that three highly conserved residues, corresponding to F290 and E293 (E2) in S2 and D316 (D3) in S3 in Shaker, constitute a