Functional modulation of brain sodium channels by cAMP-dependent phosphorylation.
Voltage-gated Na+ channels, which are responsible for the generation of action potentials in brain, are phosphorylated by cAMP-dependent protein kinase in vitro and in intact neurons. Phosphorylation by cAMP-dependent protein kinase reduces peak Na+ currents 40%--50% in membrane patches excised from rat brain neurons or from CHO cells expressing type IIA Na+ channels. Inhibition of basal cAMP-dependent protein kinase activity by transfection with a plasmid encoding a dominant negative mutant regulatory subunit increases Na+ channel number and activity, indicating that even the basal level of kinase activity is sufficient to reduce Na+ channel activity significantly. Na+ currents in membrane patches from kinase-deficient cells were reduced up to 80% by phosphorylation by cAMP-dependent protein kinase. These effects could be blocked by a specific peptide inhibitor of cAMP-dependent protein kinase and reversed by phosphoprotein phosphatases. Convergent modulation of brain Na+ channels by neurotransmitters acting through the cAMP and protein kinase C signaling pathways may result in associative regulation of electrical activity by different synaptic inputs.
Li
M
M
Department of Pharmacology, University of Washington, Seattle 98195.
West
J W
JW
Lai
Y
Y
Scheuer
T
T
Catterall
W A
WA
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000172:deficiency; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*
D015222:Sodium Channels; D000242:Cyclic AMP; D011494:Protein Kinases