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Fast Na
Volume 270,
Number 20,
Issue of May 19, pp. 12025-12034, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Subunit in
Fast Inactivation
channel inactivation is thought to
occur by the binding of an intracellular inactivation gate to regions
around or within the Na
channel pore through
hydrophobic interactions. Previous studies indicate that the
intracellular loop between domains III and IV of the Na
channel
subunit (L) forms the inactivation
gate. A three-residue hydrophobic motif (IFM) is an essential
structural feature of the gate and may serve as an inactivation
particle that binds within the pore. In this study, we used
alanine-scanning mutagenesis to examine the functional role of amino
acid residues in transmembrane segment IVS6 of the Na
channel
subunit in fast inactivation. Mutant F1764A, in the
center of IVS6, and mutant V1774A, near its intracellular end,
exhibited substantial sustained Na currents at the end
of 30-ms depolarizations. The double mutation F1764A/V1774A almost
completely abolished fast inactivation, demonstrating a critical role
for these amino acid residues in the process of inactivation. Single
channel analysis of these three mutants revealed continued reopenings
late in 40-ms depolarizing pulses, indicating that the stability of the
inactivated state was substantially impaired compared with wild type.
In addition, the cumulative first latency distribution for the V1774A
mutation contained a new component arising from opening transitions
from the destabilized inactivated state. Substitution of multiple amino
acid residues showed that the disruption of inactivation was not
correlated with the hydrophobicity of the substitution at position
1774, in contrast to the expectation if this residue interacts directly
with the IFM motif. Thermodynamic cycle analysis of simultaneous
mutations in the IFM motif and in IVS6 suggested that mutations in
these two regions independently disrupt inactivation, consistent with
the conclusion that they do not interact directly. Furthermore, a
peptide containing the IFM motif (acetyl-KIFMK-amide) restored
inactivation to the F1764A/V1774A IVS6 mutant, indicating that the
binding site for the IFM motif remains intact in these mutants. These
results suggest that the amino acid residues 1764 and 1774 in IVS6 do
not directly interact with the IFM motif of the inactivation gate but
instead play a novel role in fast inactivation of the Na
channel.
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