Fig. 4.

Allosteric model in which the channel gate opens in two sequential steps. (A) Diagram showing in each row the states corresponding to the different combination of the four voltage sensors either in the resting or active position with voltage-dependent rates α(V) and β(V). Columns depict a single gate that opens in two steps; the first governed by rates σ and ε connect to an intermediate closed state that then opens and closes with rates δ and γ, respectively. With the activation of each voltage sensor these transitions are favored by allosteric constant D and E. These allosteric constants will influence the forward rate by a fraction θ, whereas the backward rates by θ−1. (B) Simulated I_K and I_g current experiments using this model with the following parameters: α = 1,880 s⁻¹, β = 21,500 s⁻¹ with z_α = 0.49 and δ_α = 0.63. Transition rates between C_0,i and C_1,i were σ = 50.4 s⁻¹ and ε = 205 s⁻¹ with z_ε and δ_ε set to 0. D was 2.75 with θ = 0.94 and δ = 0.9 s⁻¹ and γ = 318, z_δ = 0.604 and δ_δ = 0.726. Allosteric constant E was set to 1. Top traces correspond to simulated ionic current (Upper) and gating current traces during depolarizing steps of increasing amplitude. A 50-ms pulse from −90 mV that sweeps from +20 to 350 mV in 20 mV increments was used to simulate I_K, whereas a 1-ms pulse spanning from −80 to 300 mV was preferred for I_g. Superimposed gating I_g (solid line) and I_K (dashed line) at the beginning of a depolarizing pulse to +200 mV is shown (Lower). (C) Simulated Q–V and P_o together with experimental data from (α/β1) BK channels. Q–V were obtained by integrating the first 500 μs of the simulated I_g at the end of the pulse. P_o was obtained by normalizing the simulated current amplitudes at the end of a 120-ms pulse. Closed circles correspond to the experimental data described in Fig. 2C, whereas open circles correspond to normalized G–V (from ref. 33). (D) Fast and slow charge movement measured during repolarization to −90 mV following a depolarizing pulse of different durations and voltages. (E) Voltage dependence of the time constants of Q_OFF and I_K in D and E; symbols correspond to data described in Fig. 3 and continuous line from simulated I_g at the same voltages and durations.