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Diagram of a voltage-gated ion channel, showing the three states: open, closed and inactivated. Ball and chain inactivation can only happen if the channel is open.
In
sodium channels, but many of the details remain unclear [3]
.
Discovery and Evidence
Biochemical evidence
The initial evidence for a ball and chain inactivation evidence came in 1977 with Clay Armstrong and Francisco Bezanilla's work [4].
The suggestion of a physical basis for non-conductance came from experiments in
intracellular side of the channel was found to mimic inactivation in non-inactivating channels [5] . Blockage of the channel by TEA is mutually exclusive with peptide-mediate blockage, suggesting that TEA competes for a inactivation binding site[6]
.
Molecular evidence
oocytes. The peptide restored inactivation to the channel, giving further support to the ball and chain model. In β2 proteins, the first three residues after the initial methionine have been identified as essential for inactivation. The initial residues have a sequence motif of phenylalanine,isoleucine and tryptophan (FIW) without which inactivation does not occur. Modifying the subsequent residues alters the speed and efficacy of inactivation without abolishing it [7]
.
Structural evidence
More recently,
aspartate at position 16. The structure of the chain domain is 4-turn alpha helix
structure.
Structure
The ball and chain domains are on the cytoplasmic side of the channel. The most precise structural studies have been carried out in
covalently [10]. Structural studies have shown that the inner pore of the potassium channel is accessible only through side slits between the cytoplasmic domains of the four α-subunits, rather than from a central route as previously thought[11]. The ball domain enters the channel through the side slits and attaches to a binding site deep in the central cavity. This process involves a conformational change, which allows the ball and chain blocker to elongate and reach the inner center of the channel [12]
.
depolarisation of the cell membrane. This frees up the alanine and asparagine residues with which the IFMT residues in the ball domain bind to. Adapted from Goldin, 2003 [13]
.
A positively charged region between the III and IV
domains of sodium channels is thought to act in a similar way [9]. The essential region for inactivation in sodium channels is four amino acid sequence made up of isoleucine, phenylalanine, methionine and threonine (IFMT) [13] The T and F interact directly with the docking site in the channel pore [14]. When voltage-gated sodium channels open
, the S4 segment moves outwards from the channel and into the extracellular side. This exposes hydrophobic residues in the S4 and S5 segments which interact with the inactivation ball. The phenylalanine of the ball interacts with the
alanine in domain III's S4-S5 segments and the asparagine in domain IV's S4-S5 segments[15]. This explains why inactivation can only occur once the channel is open.
Lateral slits are also present in sodium channels [16], suggesting that the access route for the ball domain may be similar.
There is a distinction between direct inactivation and two-step inactivation. Direct inactivation, which occurs in Shaker potassium channels results from the direct blockage of the channel by the ball protein, while two-step inactivation, thought to occur in BK channels, requires an intermediate binding step. [17].
Effects on neuronal firing
The interplay between opening and inactivation controls the
sodium channels this process is modulated by β subunits. The β1 subunit aids recovery from inactivation [19], while β2 accelerates inactivation [20]. The β sunubits can also interfere with ball and chain domains by blocking their entry into the channel. This leads to persistent currents, caused by the continued influx of ions. The β3 subunit can increase peristent current in certain sodium channels [13]
.
Implications for Disease
Differences in persistent and resurgent currents have been implicated in certain human
cardiac sodium channels affect inactivation. These increase persistent current by interfering with inactivation, though different mutations have opposite effects in inactivation speed [23]
.
Mutations in the
skeletal muscles are also associated with myotonia. The characteristic muscular hyperexcitation of mytonia is mainly caused by the presence sodium channels which do not inactivate, causing high levels of persistent current in the muscles [24]
.
Inactivation Prevention Domain
stoichiometric, as the gradual introduction of un-tethered synthetic balls to the cytoplasm eventually restores inactivation [26]
