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Volume 17, Number 16, Issue of August 15, 1997 pp. 6086-6093
Copyright ©1997 Society for Neuroscience

Phosphorylation at a Single Site in the Rat Brain Sodium Channel Is Necessary and Sufficient for Current Reduction by Protein Kinase A

Received April 18, 1997; revised May 28, 1997; accepted June 2, 1997.

Raymond D. Smith and Alan L. Goldin

Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697-4025

Voltage-gated sodium channels respond to excitatory inputs in nerve cells, generating spikes of depolarization at axon hillock regions and propagating the initial rising phase of action potentials through axons. It previously has been shown that protein kinase A (PKA) attenuates sodium current amplitude 20-50% by phosphorylating serines located in the I-II linker of the sodium channel. We have tested the individual contributions of five PKA consensus sites in the I-II linker by measuring sodium currents expressed in Xenopus oocytes during conditions of PKA induction. PKA was induced by perfusing oocytes with a cocktail that contained forskolin, chlorophenylthio-cAMP, dibutyryl-cAMP, and 3-isobutyl-1-methylxanthine. Phosphorylation at the second PKA site (serine-573) was necessary and sufficient to diminish sodium current amplitude. Phosphorylation at the third and fourth positions (serine-610 and serine-623) reduced current amplitude, but the effect was considerably smaller at those positions. Introduction of a negative charge at site 2 by substitution of serine-573 with an aspartate constitutively reduced the basal level of sodium current, indicating that the attenuation of sodium current by phosphorylation of site 2 by PKA results from the introduction of a negative charge at this site.

Key words: ion channel; modulation; cAMP; site-directed mutagenesis; sodium channel; phosphorylation; protein kinase A; Xenopus oocytes; forskolin

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