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J. Biol. Chem., Vol. 259, Issue 13, 8210-8218, Jul, 1984
MR Costa and WA Catterall
In purified preparations of voltage-sensitive sodium channels, the alpha
subunit is selectively phosphorylated by cAMP-dependent protein kinase
(Costa, M. R. C., Casnellie, J. E., and Catterall, W. A. (1982) J. Biol.
Chem., 7918-7921). We have developed methods to measure sodium channel
phosphorylation in both lysed synaptosomal membranes and intact
synaptosomes. Incubation of lysed synaptosomal membranes with exogenously
added catalytic subunit of cAMP-dependent kinase and [gamma- 32P]ATP
resulted in rapid phosphorylation of the alpha subunit as detected by
specific immuno-precipitation, sodium dodecyl sulfate-gel electrophoresis,
and autoradiography. Analysis of tryptic phosphopeptides revealed five
major sites of reaction. The level of phosphorylation of these sites on the
sodium channel in intact synaptosomes was monitored using a
rephosphorylation method in which those sites not phosphorylated in situ
were labeled with [gamma-32P]ATP and exogenously added protein kinase after
lysis of the synaptosomes. Incubation of synaptosomes with 8-Br-cAMP
completely blocked labeling of the alpha subunit in rephosphorylation
indicating marked stimulation of phosphorylation of the sites on the sodium
channel in situ. Phosphorylation was complete in 15 s and all four of the
tryptic phosphopeptides detected under these conditions could be
phosphorylated in situ. These results show that the sodium channel can be
rapidly phosphorylated by endogenous cAMP-dependent protein kinase in
intact synaptosomes. In addition, since ATP and protein kinase are only
available inside the synaptosomes, they also show that the alpha subunit is
a transmembrane polypeptide exposed on both sides of the synaptosomal
membrane. The functional consequences of 8-Br-cAMP- stimulated
phosphorylation were examined using ion flux and neurotoxin- binding
methods. Binding of saxitoxin and scorpion toxin were unaffected, but
neurotoxin-activated 22Na+ influx mediated by the sodium channel was
reduced 16 to 26% (P less than 0.01) under various experimental conditions.
The potential physiological significance of this action is considered.
Cyclic AMP-dependent phosphorylation of the alpha subunit of the sodium channel in synaptic nerve ending particles
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