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The Journal of Neuroscience, July 1, 1999, 19(13):5301-5310
Voltage-Dependent Neuromodulation of Na+ Channels by
D1-Like Dopamine Receptors in Rat Hippocampal Neurons
Angela R.
Cantrell,
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
through phosphorylation of the  subunit of the
Na+ channel by cAMP-dependent protein kinase (PKA).
Here we report that neuromodulation of Na+ currents
by DA receptors via PKA is voltage-dependent in the range of  110 to
70 mV and is also sensitive to concurrent activation of protein
kinase C (PKC). Depolarization enhanced the ability of D1-like DA
receptors to reduce peak Na+ currents via the PKA
pathway. Similar voltage-dependent modulation was observed when PKA was
activated directly with the membrane-permeant PKA activator DCl-cBIMPS
(cBIMPS; 20 µM), indicating that the membrane potential
dependence occurs downstream of PKA. PKA activation caused only a small
(2.9 mV) shift in the voltage dependence of steady-state inactivation
and had no effect on slow inactivation or on the rates of entry into
the fast or slow inactivated states, suggesting that another mechanism
is responsible for coupling of membrane potential changes to PKA
modulation. Activation of PKC with a low concentration of the
membrane-permeant diacylglycerol analog oleylacetyl glycerol also
potentiated modulation by SKF 81297 or cBIMPS, and these effects were
most striking at hyperpolarized membrane potentials where PKA
modulation was not stimulated by membrane depolarization. Thus,
activation of D1-like DA receptors causes a strong reduction in
Na+ current via the PKA pathway, but it is effective
primarily when it is combined with depolarization or activation of PKC.
The convergence of these three distinct signaling modalities on the
Na+ channel provides an intriguing mechanism for
integration of information from multiple signaling pathways in the
hippocampus and CNS.
Key words:
Na+ current; neuromodulation; cAMP-dependent protein kinase; protein kinase C; hippocampus; dopamine
receptors; phosphorylation
Copyright © 1999 Society for Neuroscience 0270-6474/99/19135301-10$05.00/0
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