Ball and chain inactivation

In neuroscience, ball and chain inactivation is a model to explain the fast inactivation mechanism of voltage-gated ion channels. The process is also called hinged-lid inactivation or N-type inactivation. A voltage-gated ion channel can be in three states: open, closed, or inactivated. The inactivated state is mainly achieved through fast inactivation, by which a channel transitions rapidly from an open to an inactivated state. The model proposes that the inactivated state, which is stable and non-conducting, is caused by the physical blockage of the pore. The blockage is caused by a "ball" of amino acids connected to the main protein by a string of residues on the cytoplasmic side of the membrane. The ball enters the open channel and binds to the hydrophobic inner vestibule within the channel. This blockage causes inactivation of the channel by stopping the flow of ions. This phenomenon has mainly been studied in potassium channels and sodium channels. The initial evidence for a ball and chain inactivation came in 1977 with Clay Armstrong and Francisco Bezanilla's work. The suggestion of a physical basis for non-conductance came from experiments in squid giant axons, showing that internal treatment with pronase disrupted the inactivation phenomenon. This suggested a physical, tethered mechanism for inactivation as the pronase was inferred to degrade the channel blocker and abolish the inactivation process. These experiments also showed that inactivation can only occur after the opening of the channel. This was done by hyperpolarising the membrane, causing the channel to open, and observing a delay in inactivation. Inactivation was not observed when the membrane was depolarised (closed). Introducing tetraethylammonium (TEA) on the intracellular side of the channel was found to mimic inactivation in non-inactivating channels. Blockage of the channel by TEA is mutually exclusive with peptide-mediate blockage, suggesting that TEA competes for an inactivation binding site.