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The Journal of Neuroscience, 1999, 19:RC21:1-6
RAPID COMMUNICATION
Dopaminergic Modulation of Voltage-Gated Na+ Current
in Rat Hippocampal Neurons Requires Anchoring of cAMP-Dependent Protein
Kinase
Angela R.
Cantrell,
Victoria C.
Tibbs,
Ruth E.
Westenbroek,
Todd
Scheuer, and
William A.
Catterall
Department of Pharmacology, University of Washington, Seattle,
Washington 98195-7280
Activation of D1-like dopamine (DA) receptors reduces peak
Na+ current in acutely isolated hippocampal neurons
via a modulatory mechanism involving phosphorylation of the
Na+ channel  subunit by cAMP-dependent protein
kinase (PKA). Peak Na+ current is reduced 20-50%
in the presence of the D1 agonist SKF 81297 or the PKA activator
Sp-5,6-dichloro-l- -D-ribofuranosyl benzimidazole-3',5'-cyclic monophosphorothionate (cBIMPS).
Co-immunoprecipitation experiments show that Na+
channels are associated with PKA and A-kinase-anchoring protein 15 (AKAP-15), and immunocytochemical labeling reveals their
co-localization in the cell bodies and proximal dendrites of
hippocampal pyramidal neurons. Anchoring of PKA near the channel by an
AKAP, which binds the RII regulatory subunit, is necessary for
Na+ channel modulation in acutely dissociated
hippocampal pyramidal neurons. Intracellular dialysis with the
anchoring inhibitor peptides Ht31 from a human thyroid AKAP and AP2
from AKAP-15 eliminated the modulation of the Na+
channel by the D1-agonist SKF 81297 and the PKA activator cBIMPS. In
contrast, dialysis with the inactive proline-substituted control peptides Ht31-P and AP2-P had little effect on the D1 and PKA modulation. Therefore, we conclude that modulation of the
Na+ channel by activation of D1-like DA receptors
requires targeted localization of PKA near the channel to achieve
phosphorylation of the subunit and to modify the functional
properties of the channel.
Key words:
Na+ current; neuromodulation; cAMP-dependent protein kinase; A-kinase-anchoring protein; hippocampus; dopamine receptors; phosphorylation
Copyright © 0000 Society for Neuroscience 0270-6474/0/$05.00/0
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