Voltage-dependent neuromodulation of Na+ channels by D1-like dopamine receptors in rat hippocampal neurons

Activation of D1-like dopamine (DA) receptors reduces peak Na+ current in a cutely isolated hippocampal neurons through phosphorylation of the cu subun it of the Na+ channel by cAMP-dependent protein kinase (PKA), Here we repor t that neuromodulation of Na+ currents by DA receptors via PKA is voltage-d ependent 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. Si milar voltage-dependent modulation was observed when PKA was activated dire ctly with the membrane-permeant PKA activator DCI-cBIMPS (cBIMPS; 20 mu M), indicating that the membrane potential dependence occurs downstream of PKA . PKA activation caused only a small (-2.9 mV) shift in the voltage depende nce 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 ch anges to PKA modulation. Activation of PKC with a low concentration of the membrane-permeant diacylglycerol analog oleylacetyl glycerol also potentiat ed modulation by SKF 81297 or cBIMPS, and these effects were most striking at hyperpolarized membrane potentials where PKA modulation was not stimulat ed by membrane depolarization. Thus, activation of D1-like DA receptors cau ses a strong reduction in Na+ current via the PKA pathway, but it is effect ive primarily when it is combined with depolarization or activation of PKC. The convergence of these three distinct signaling modalities on the Na+ ch annel provides an intriguing mechanism for integration of information from multiple signaling pathways in the hippocampus and CNS.