Depolarization of rat brain synaptosomes increases phosphorylation of voltage-sensitive sodium channels.
Depolarization of rat brain synaptosomes causes an increase in phosphorylation of serine residues 573, 610, 623, and 687 on voltage-sensitive sodium channels. Although these sites have been shown to be phosphorylated by cAMP-dependent protein kinase in vitro and in situ, the depolarization-induced increase in their state of phosphorylation is not due to increased cAMP-dependent protein kinase activity, but requires calcium influx and protein kinase C. Since phosphorylation at this cluster of sites inhibits sodium current and would decrease neuronal excitability, this may be an important negative feedback mechanism whereby calcium influx during prolonged or repetitive depolarization can attenuate neuronal excitability and prevent further calcium accumulation. Phosphorylation of purified channels by protein kinase C decreases dephosphorylation of cAMP-dependent phosphorylation sites by purified calcineurin or protein phosphatase 2A. This suggests that one mechanism by which protein kinase C may increase phosphorylation of cAMP-dependent phosphorylation sites in sodium channels is to inhibit their dephosphorylation. This represents an important new mechanism for convergent regulation of an ion channel by two distinct signal transduction pathways.
Kondratyuk
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Department of Veterinary Pathobiology, Purdue University, West Lafayette, Indiana 47907-1153, USA.
Rossie
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D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000166:cytology*; D019703:Calcineurin; D002118:Calcium / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D008564:Membrane Potentials; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism*; D013574:Synaptosomes / Q000502:physiology*
D002148:Calmodulin-Binding Proteins; D015222:Sodium Channels; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D002118:Calcium