Ion-channel deactivation and ion-channel inactivation are different. Ion-channel deactivation closes an activation gate when the voltage returns toward rest. Ion-channel inactivation makes a channel unavailable even while depolarization remains favorable for activation. A minimal kinetic picture is a closed state, an open state and an unavailable state, with recovery required before reopening. This helps terminate inward electric current and produces a neuronal refractory period.
In rapid voltage-gated potassium channel N-type inactivation, a cytoplasmic terminal segment, sometimes supplied by an auxiliary subunit, blocks the open inner pore. The classic ball-and-chain inactivation picture is supported by loss of rapid ion-channel inactivation after removing the relevant terminal segment and restoration by an appropriate soluble peptide. This links a mobile structural element to open-pore blockade; it does not imply that all potassium channels use that mechanism.[ref]
Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB by William N. Zagotta and others. 1990 primary study, restoration of rapid inactivation
Slower C-type inactivation involves rearrangement near the selectivity filter and external pore. Dependence on pore structure, ion occupancy and extracellular ions distinguishes it from a simple cytoplasmic plugging particle. Different channels can combine several unavailable states, so a single recovery time constant need not describe every trace.
Fast ion-channel inactivation in canonical animal voltage-gated sodium channels involves the intracellular linker between domains III and IV, including its hydrophobic IFM motif, and is coupled to domain-IV voltage-sensor activation. The modern structural interpretation is an allosteric latch acting on the gate, rather than a universal literal particle sitting in the ion pathway. The older hinged-lid analogy is useful only with that qualification.[ref]
https://www.nature.com/articles/s41467-022-30400-w/. 2022 primary structural study, discussion distinguishes IFM-mediated allosteric inactivation from an observed alternative N-terminal pore block
Functionally, a voltage clamp trace shows electric current declining during a maintained step; a second test pulse measures recovery of availability. Holding-potential dependence separates an altered fraction of available channels from a mere change in maximal open electrical conductance. Persistent electric current after defective ion-channel inactivation, or delayed recovery that reduces subsequent responses, illustrates why both entry into and exit from unavailable states matter for excitability. A decaying macroscopic electric current alone does not uniquely identify the molecular mechanism.
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