| Autor: |
Few, W. Preston, Scheuer, Todd, Catterall, William A. |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 3/20/2007, Vol. 104 Issue 12, p5187-5192, 6p |
| Abstrakt: |
In hippocampal pyramidal cells, dopamine acts at D1 receptors to reduce peak Na+ currents by activation of phosphorylation by PKA anchored via an A kinase-anchoring protein (AKAP15). However, the mechanism by which AKAP15 anchors PKA to neuronal Na+ channels is not known. By using a strategy of coimmunoprecipitation from transfected tsA-201 cells, we have found that AKAP15 directly interacts with Nav1.2a channels via the intracellular loop between domains land II. This loop contains key functional phosphorylation sites. Mutagenesis indicated that this interaction occurs through a modified leucine zipper motif near the N terminus of the loop. Whole-cell patch clamp recordings of acutely dissociated hippocampal pyramidal cells revealed that the Dl dopamine receptor agonist SKF 81297 reduces peak Na+ current amplitude by 20.5%, as reported previously. Disruption of the leucine zipper interaction between Nav1.2a and AKAP15 through the inclusion of a small competing peptide in the patch pipette inhibited the SKF 81297-induced reduction in peak Na+ current, whereas a control peptide with mutations in amino acids important for the leucine zipper interaction did not. Our results define the molecular mechanism by which G protein-coupled signaling pathways can rapidly and efficiently modulate neuronal excitability through local protein phosphorylation of Na+ channels by specifically anchored PKA. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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