In ball-and-chain inactivation, also called N-type inactivation, a flexible intracellular N-terminal region carries an inactivation particle. Once a voltage-gated potassium channel opens, this tethered particle can enter and occlude the inner pore, stopping electric current even while the activation machinery favors an open configuration. Recovery requires the particle to leave, after which the activation gate can return to its resting conformation. This supplies an additional unavailable state, not merely reversal of activation.
The decisive evidence separates necessity from sufficiency. Removing the relevant N-terminal region greatly reduces fast ion-channel inactivation while preserving activation. Applying a peptide corresponding to the missing N-terminal region on the cytoplasmic side restores blocking with similar properties. Changes in the blocking region alter blocking kinetics, and altering the tether affects the rate at which the particle reaches the pore. Open-pore access and competition with intracellular pore blockers support occlusion of the inner cavity. A tether makes the particle's local effective concentration high, explaining rapid intramolecular block.[ref]
Biophysical and molecular mechanisms of Shaker potassium channel inactivation by Toshinori Hoshi and others. N-terminal perturbations separate rapid inactivation from activation
[ref]Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB by William N. Zagotta and others. Cytoplasmic N-terminal peptide restores inactivation in deletion mutants
This mechanism is distinct from slower filter-associated C-type inactivation. An N-terminal particle is a mechanism for certain potassium ion channels, not a universal explanation of all ion-channel inactivation.
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