Past exam of the biological physics course of the University of Oxford / 2015 / 2 / e / Solution

In classical ball-and-chain inactivation, a cytoplasmic N-terminal part of the voltage-gated potassium channel acts as a tethered blocking particle. Once the pore opens, this particle reaches and occludes its intracellular entrance. The flexible connecting segment allows access; removal of the block permits recovery. Thus opening and subsequent loss of conduction can occur even while the activating voltage remains applied.

Several independent observations support this mechanism. Removing or disrupting the N-terminal inactivation segment suppresses fast ion-channel inactivation while leaving activation possible. An appropriate soluble peptide applied from the cytoplasmic side restores an open-channel block in otherwise noninactivating channels. Changes in the blocking segment alter block kinetics, while changing its access or tether can alter how rapidly it finds the pore. Rescue in trans is particularly informative: the blocking particle need not remain covalently attached to produce the effect.^[ref][ref]

This mechanism is N-type inactivation. It should not be generalized to every potassium ion channel: C-type inactivation instead involves changes associated with the outer pore and selectivity filter.