Abstract
Kv1.4 encodes a slowly recovering transient outward current (I(to)),
which inactivates by a fast N-type (intracellular ball and chain)
mechanism but has slow recovery due to C-type inactivation. C-type
inactivation of the NH(2)-terminal deletion mutant (fKv1.4DeltaN)
was inhibited by 98 mM extracellular K$^+$ concentration (K$^+$(o)),
whereas N-type was unaffected. In 98 mM K$^+$(o), removal of
intracellular K$^+$ concentration (K$^+$(i)) speeded C-type
inactivation but had no effect on N-type inactivation, suggesting
that C-type inactivation is sensitive to K$^+$ binding to intracellular
sites. C-type inactivation is thought to involve closure of the extracellular
pore mouth. However, a valine to alanine mutation on the intracellular
side of S6 (V561A) of fKv1.4DeltaN alters recovery and results in
anomalous speeding of C-type inactivation with increasing K$^+$(o).
Extracellular pH (pH(o)) modulated both N- and C-type inactivation
through an S5-H5 linker histidine (H508) with acidosis speeding both
N- and C-type inactivation. Mutation of an extracellular lysine to
a tyrosine (K532Y) slowed C-type inactivation and inhibited the pH
dependence of both N- and C-type inactivation. These results suggest
that mutations, K$^+$, and pH modulate inactivation through
membrane-spanning mechanisms involving S6.
- -u.s.
- 12388308
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