CONVERGENT REGULATION OF SODIUM-CHANNELS BY PROTEIN-KINASE-C AND CAMP-DEPENDENT PROTEIN-KINASE

The function of voltage-gated sodium channels that are responsible for action potential generation in mammalian brain neurons is modulated b y phosphorylation by adenosine 3',5'-monophosphate (cAMP)-dependent pr otein kinase (cA-PK) and by protein kinase C (PKC). Reduction of peak sodium currents by cA-PK in intact cells required concurrent activatio n of PKC and was prevented by blocking phosphorylation of serine 1506, a site in the inactivation gate of the channel that is phosphorylated by PKC but not by cA-PK. Replacement of serine 1506 with negatively c harged amino acids mimicked the effect of phosphorylation. Conversion of the consensus sequence surrounding serine 1506 to one more favorabl e for cA-PK enhanced modulation of sodium currents by cA-PK. Convergen t modulation of sodium channels required phosphorylation of serine 150 6 by PKC accompanied by phosphorylation of additional sites by cA-PK. This regulatory mechanism may serve to integrate neuronal signals medi ated through these parallel signaling pathways.