Potentiation of rat brain sodium channel currents by PKA in Xenopus oocytes involves the I-II linker

Functional modulation of voltage-gated sodium channels affects the electric al excitability of neurons. Protein kinase A (PKA) can decrease sodium curr ents by phosphorylation at consensus sites in the cytoplasmic I-II linker. Once the sites are phosphorylated, however, additional PKA activity can inc rease sodium currents by an unknown mechanism. When the PKA sites were elim inated by substitutions of alanine for serine, peak sodium current amplitud es were increased by 20-80% when PKA was activated in Xenopus oocytes eithe r by stimulation of a coexpressed beta(2)-adrenergic receptor or by perfusi on with reagents that increase cAMP. Potentiation required the I-II linker of the brain channel, in that a chimeric channel in which the brain linker was replaced with the comparable linker from the skeletal muscle channel di d not demonstrate potentiation. Using a series of chimeric and deleted chan nels, we demonstrate that potentiation is not dependent on any single regio n of the linker and that the extent of potentiation varies depending on the total length and the residues throughout the Linker. These data are consis tent with the hypothesis that potentiation by PKA is an indirect process in volving phosphorylation of an accessory protein that interacts with the I-I I linker of the sodium channel.