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Science 10 September 1993:
Vol. 261. no. 5127, pp. 1439 - 1442
DOI: 10.1126/science.8396273
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Articles

Science, Vol 261, Issue 5127, 1439-1442
Copyright © 1993 by American Association for the Advancement of Science

articles

Convergent regulation of sodium channels by protein kinase C and cAMP-dependent protein kinase

M Li, JW West, R Numann, BJ Murphy, T Scheuer, and WA Catterall

Department of Pharmacology, University of Washington, Seattle 98195.

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.


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