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The Journal of Neuroscience, January 12, 2005, 25(2):507-513; doi:10.1523/JNEUROSCI.4089-04.2005

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Cellular/Molecular
Specific Modulation of Na⁺ Channels in Hippocampal Neurons by Protein Kinase C

Yuan Chen,¹ Angela R. Cantrell,¹ Robert O. Messing,² Todd Scheuer,¹ and William A. Catterall¹

¹Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, and ²Ernest Gallo Clinic and Research Center, Department of Neurology, University of California at San Francisco, Emeryville, California 94608

Acetylcholine binding to muscarinic acetylcholine receptors activates G-proteins, phospholipase C, and protein kinase C (PKC), which phosphorylates brain Na⁺ channels and reduces peak Na⁺ current in hippocampal neurons. Because multiple PKC isozymes with different regulatory properties are expressed in hippocampal neurons, we investigated which ones are responsible for mediating this effect. The diacylglycerol analog oleoylacetylglycerol (OAG) reduced the amplitude of Na⁺ current in dissociated mouse hippocampal neurons by 28.5 ± 5.3% (p < 0.01). The reduction of peak Na⁺ current was similar with Ca²⁺-free internal solution and in 92 nM internal Ca²⁺, suggesting that calcium-dependent, conventional PKC isozymes were unlikely to mediate this response. Gö6976, which inhibits conventional PKC isozymes, reduced the effect of PKC activators only slightly, whereas rottlerin, which inhibits PKC preferentially at 5 µM, had no effect. Ro-31-8425 (20 nM), which inhibits conventional PKC isozymes, did not reduce the response to OAG. However, higher concentrations of Ro-31-8425 (100 nM or 1 µM) that inhibit novel PKC isozymes effectively blocked OAG inhibition of Na⁺ current. Inclusion of a selective PKC-anchoring inhibitor peptide (PKC-I) in the recording pipette prevented the reduction of peak Na⁺ current by OAG, whereas an anchoring inhibitor peptide specific for PKC and an inactive scrambled PKC-I peptide had no effect. In addition, OAG had no effect on Na⁺ current in hippocampal neurons from PKC null mice. Overall, our data from four experimental approaches indicate that anchored PKC is the isozyme responsible for PKC-mediated reduction of peak Na⁺ currents in mouse hippocampal neurons.

Key words: action potential; channel; excitability; hippocampus; neuromodulation; phosphorylation; protein kinase; pyramidal; sodium [Na]; voltage clamp

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Received Oct 1, 2004; revised November 22, 2004; accepted November 23, 2004.

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