Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 2, Pages 507-513Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4089-04.2005
Keywords
action potential; channel; excitability; hippocampus; neuromodulation; phosphorylation; protein kinase; pyramidal; sodium [Na]; voltage clamp
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Funding
- NIMH NIH HHS [K01 MH01669] Funding Source: Medline
- NINDS NIH HHS [R01 NS015751, R01 NS15751] Funding Source: Medline
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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. Go6976, which inhibits conventional PKC isozymes, reduced the effect of PKC activators only slightly, whereas rottlerin, which inhibits PKC delta preferentially at 5 mu M, 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 mu M) that inhibit novel PKC isozymes effectively blocked OAG inhibition of Na(+)current. Inclusion of a selective PKC epsilon-anchoring inhibitor peptide (PKC epsilon-I) in the recording pipette prevented the reduction of peak Na+ current by OAG, whereas an anchoring inhibitor peptide specific for PKC beta and an inactive scrambled PKC epsilon-I peptide had no effect. In addition, OAG had no effect on Na+ current in hippocampal neurons from PKC epsilon null mice. Overall, our data from four experimental approaches indicate that anchored PKC epsilon is the isozyme responsible for PKC-mediated reduction of peak Na+ currents in mouse hippocampal neurons.
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