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Subunit of Brain
Sodium Channels
Department of Pharmacology, University of Washington, Seattle,
Washington 98195 (V.L.T., J.C.M., H.B.-B., C.B., T.S., W.A.C.), and
Roussel Uclaf, 92320 Romainville, France (D.B., J.-P.D., D.G.)
Na+ channels are the primary molecular targets of the
pyrethroid insecticides. Na+ channels consisting of only a
type IIA 
subunit expressed in Chinese hamster ovary cells responded
to pyrethroid treatment in a normal manner: a sustained Na+
current was induced progressively after each depolarizing pulse in a
train of stimuli, and this Na+ current decayed slowly on
repolarization. These modified Na+ channels could be
reactivated at much more negative membrane potentials
(V0.5 = 
139 mV) than unmodified
Na+ channels (V0.5 = 28 mV).
These results indicate that pyrethroids can modify the functional
properties of the Na+ channel subunit expressed alone
by blocking their inactivation, shifting their voltage dependence of
activation, and slowing their deactivation. To demonstrate directly the
specific interaction of pyrethroids with the subunit of
voltage-gated Na+ channels, a radioactive photosensitive
derivative, [3H]RU58487, was used in binding and
photolabeling studies. In the presence of a low concentration of the
nonionic detergent Triton X-100, specific pyrethroid binding to
Na+ channels in rat brain membrane preparations could be
measured and reached 75% of total binding under optimal conditions.
Binding approached equilibrium within 1 hr at 4°, dissociated with a
half-time of ~10 min, and had KD values of
~58-300 nM for three representative pyrethroids.
Specific pyrethroid binding was enhanced by ~40% in the presence of
100 nM -scorpion toxin, but no allosteric enhancement
was observed in the presence of toxins acting at other Na+
channel receptor sites. Extensive membrane washing increased specific
binding to 89%. Photolabeling with [3H]RU58487 under
these optimal binding conditions revealed a radiolabeled band with an
apparent molecular mass of 240 kDa corresponding to the Na+
channel subunit. Anti-peptide antibodies recognizing sequences within the subunit were able to specifically immunoprecipitate the
covalently modified channel. Together, these results demonstrate that
the pyrethroids can modify the properties of cells expressing only the
subunit of Na+ channels and can bind specifically to a
receptor site on the subunit.
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