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 by phosphorylation by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (cA-PK) and by protein kinase C (PKC). Reduction of peak sodium currents by cA-PK in intact cells required concurrent activation 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 charged amino acids mimicked the effect of phosphorylation. Conversion of the consensus sequence surrounding serine 1506 to one more favorable for cA-PK enhanced modulation of sodium currents by cA-PK. Convergent modulation of sodium channels required phosphorylation of serine 1506 by PKC accompanied by phosphorylation of additional sites by cA-PK. This regulatory mechanism may serve to integrate neuronal signals mediated through these parallel signaling pathways.
Department of Pharmacology, University of Washington, Seattle 98195.
M
M
Li
J W
JW
West
R
R
Numann
B J
BJ
Murphy
T
T
Scheuer
W A
WA
Catterall
D000200:Action Potentials; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D016384:Consensus Sequence; D006224:Cricetinae; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*
D015222:Sodium Channels; D012964:Sodium; D011494:Protein Kinases; D011493:Protein Kinase C