Voltage-Dependent Neuromodulation of Na⁺Channels by D1-Like Dopamine Receptors in Rat Hippocampal Neurons

Abstract

Activation of D1-like dopamine (DA) receptors reduces peak Na+ current in acutely isolated hippocampal neurons through phosphorylation of the alpha 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 microM), 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.

Fibroblast Growth Factor Homologous Factor 1B Binds to the C Terminus of the Tetrodotoxin-resistant Sodium Channel rNav1.9a (NaN)

“…Skeletal and cardiac muscle sodium channels interact directly with the cytoskeletal element syntrophin, which may determine their localization (10). The interaction of brain sodium channels with AKAP15 is required for dopaminergic modulation (11). More recently, the C-terminal polypeptide of rNa v 1.2 (brain type II) was shown to bind calmodulin, suggesting modulation of these channels by Ca 2ϩ (23), and the rNa v 1.2-L1 was shown to interact with synaptotagmin in a Ca 2ϩ -regulated manner (46).…”

“…The C terminus of skeletal muscle and cardiac muscle ␣-subunits, SkM1 and SkM2, respectively, bind to syntrophin via their PDZ domain, thus linking these channels to the cortical actin network and extracellular matrix through the association of syntrophin with the dystrophin-associated protein complex (10). Brain ␣-subunits are phosphorylated at specific serine/threonine sites by protein kinase A that is anchored to the ␣-subunit via AKAP15 (11,12). Receptor protein-tyrosine phosphatase (RPTP␤) interacts with brain ␣-subunits via its carbonic anhydrase homology extracellular domain and its intracellular phosphatase domain and phosphorylates tyrosine residues of the channel (13).…”

Repeated Amphetamine Administration Decreases D1Dopamine Receptor-Mediated Inhibition of Voltage-Gated Sodium Currents in the Prefrontal Cortex

“…4), indicating that the I NaT capacity of mPFC neurons taken from both treatment groups is similar in the absence of PKA activity. A key aspect of PKA modulation of I NaT is its voltage dependence (Cantrell et al, 1999;Carr et al, 2003). Cantrell et al (1999) demonstrated in hippocampal neurons and Carr et al (2003) demonstrated in mPFC neurons that PKA-induced inhibition of I NaT is reduced when holding neurons at more hyperpolarized potentials (e.g., Ϫ90 mV).…”

Repeated Cocaine Administration Decreases Calcineurin (PP2B) but Enhances DARPP-32 Modulation of Sodium Currents in Rat Nucleus Accumbens Neurons

“…It is well established that Na þ channels are under dynamic control of phosphorylation/dephosphorylation Schiffmann et al, 1998), in which calcineurin (CaN), a Ca 2þ / calmodulin-dependent serine/threonine protein phosphatase (also known as protein phosphatase 2B, PP2B), plays a significant role (see Catterall, 1997;Yakel, 1997;Herzig and Neumann, 2000;Greengard, 2001;Shibasaki et al, 2002 for a review). For instance, while cAMP-dependent protein kinase A (PKA) phosphorylates Na þ channels, which leads to a decrease in I Na (Li et al, 1992;Cantrell et al, 1999;Smith and Goldin, 1997), CaN dephosphorylates specific serine sites in the intracellular loop of type II-Aa subunit of Na þ channels (Murphy et al, 1993) and enhances I Na (Hu et al, 2005). Although PKA-activated p-Thr.34-DARPP-32 reduces I Na , CaN inhibits this action of p-Thr.34-DARPP-32 Schiffmann et al, 1998).…”