Past exam of the biological physics course of the University of Oxford / 2021 / 1 / a / Solution

At the initial negative membrane potential, most voltage-gated potassium channels have a closed activation gate. Depolarization moves charged residues in each voltage-sensing domain, particularly the S4 helices, through the electric field. Coupling between the voltage-sensing domains and the pore opens the intracellular gate. A classical voltage-gated potassium channel has four subunits, each with six transmembrane helices; S5, the pore loop and S6 contribute to the central pathway and selectivity filter. The rising open probability produces increasing outward potassium electric current, since the imposed positive membrane potential is above the potassium Nernst equilibrium potential. Here outward electric current is positive: $I_K=N\gamma p_O(V-E_K)$, where $N$ is channel number and $\gamma$ is single-channel electrical conductance.

The electric current subsequently falls because the rapidly inactivating Shaker form exhibits ball-and-chain inactivation. An intracellular N-terminal domain, tethered to the channel, blocks the open pore. The ion channel can therefore stop conducting while the membrane potential remains depolarized and the activation machinery remains activated. This is ion-channel inactivation, rather than reversal of the voltage step, loss of the ionic driving force, or ordinary gate closure. Repolarization favors removal of the block and recovery of channel availability. Slower C-type inactivation involving the outer pore can coexist, but is not the principal explanation of the rapid decay described here.

Several independent observations connect this functional explanation to structure. Small transient gating electric currents report movement of sensor electric charge before ionic conduction; charge-neutralization studies of S4/S2 change the measured gating charge and activation. Structural studies resolve separate sensor and pore regions.^[ref][ref] Historical N-terminal removal abolished rapid ion-channel inactivation while preserving activation, and the corresponding free peptide restored block from the cytoplasmic side. These results separate the activation gate from the tethered blocker and identify which side of the cell membrane contains the blocking domain.^[ref][ref]

Source-gap TODO: the supplied PDF's figure invokes an undefined image object, so its actual pulse duration, pulse sequence, current scale, peak amplitude, decay time and any tail-current waveform cannot be read. The account above uses only the stated change from $-60$ to $+20\mathrm{mV}$ and the stated rise and rapid decay; no numerical kinetic fit or reconstruction of the missing trace is claimed.