RGD Reference Report - Dopamine modulation of neuronal Na(+) channels requires binding of A kinase-anchoring protein 15 and PKA by a modified leucine zipper motif. - Rat Genome Database

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Dopamine modulation of neuronal Na(+) channels requires binding of A kinase-anchoring protein 15 and PKA by a modified leucine zipper motif.

Authors: Few, WP  Scheuer, T  Catterall, WA 
Citation: Few WP, etal., Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5187-92. Epub 2007 Mar 14.
RGD ID: 2317301
Pubmed: PMID:17360357   (View Abstract at PubMed)
PMCID: PMC1829284   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0611619104   (Journal Full-text)

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 Na(v)1.2a channels via the intracellular loop between domains I and 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 D1 dopamine receptor agonist SKF 81297 reduces peak Na(+) current amplitude by 20.5%, as reported previously. Disruption of the leucine zipper interaction between Na(v)1.2a 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.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
leucine zipper domain binding  IPIAkap7 (Rattus norvegicus)2317301 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Scn2a  (sodium voltage-gated channel alpha subunit 2)


Additional Information