D₁ Dopamine Receptor Activation Reduces GABA_A Receptor Currents in Neostriatal Neurons Through a PKA/DARPP-32/PP1 Signaling Cascade

Abstract

Dopamine is a critical determinant of neostriatal function, but its impact on intrastriatal GABAergic signaling is poorly understood. The role of D(1) dopamine receptors in the regulation of postsynaptic GABA(A) receptors was characterized using whole cell voltage-clamp recordings in acutely isolated, rat neostriatal medium spiny neurons. Exogenous application of GABA evoked a rapidly desensitizing current that was blocked by bicuculline. Application of the D(1) dopamine receptor agonist SKF 81297 reduced GABA-evoked currents in most medium spiny neurons. The D(1) dopamine receptor antagonist SCH 23390 blocked the effect of SKF 81297. Membrane-permeant cAMP analogues mimicked the effect of D(1) dopamine receptor stimulation, whereas an inhibitor of protein kinase A (PKA; Rp-8-chloroadenosine 3',5' cyclic monophosphothioate) attenuated the response to D(1) dopamine receptor stimulation or cAMP analogues. Inhibitors of protein phosphatase 1/2A potentiated the modulation by cAMP analogues. Single-cell RT-PCR profiling revealed consistent expression of mRNA for the beta1 subunit of the GABA(A) receptor-a known substrate of PKA-in medium spiny neurons. Immunoprecipitation assays of radiolabeled proteins revealed that D(1) dopamine receptor stimulation increased phosphorylation of GABA(A) receptor beta1/beta3 subunits. The D(1) dopamine receptor-induced phosphorylation of beta1/beta3 subunits was attenuated significantly in neostriata from DARPP-32 mutants. Voltage-clamp recordings corroborated these results, revealing that the efficacy of the D(1) dopamine receptor modulation of GABA(A) currents was reduced in DARPP-32-deficient medium spiny neurons. These results argue that D(1) dopamine receptor stimulation in neostriatal medium spiny neurons reduces postsynaptic GABA(A) receptor currents by activating a PKA/DARPP-32/protein phosphatase 1 signaling cascade targeting GABA(A) receptor beta1 subunits.

Dopaminergic Modulation of Axon Collaterals Interconnecting Spiny Neurons of the Rat Striatum

“…Bicuculline-sensitive currents, evoked intrastriatally, were significantly reduced by the D 1 agonist ( p Ͻ 0.01) (Fig. 7F ) (Flores-Hernández et al, 2000;Gao et al, 2003). In some cases IPSC amplitude did not change, as seen in the time course of Figure 8 D. This is opposite from the findings after antidromic GP stimulation.…”

“…On the other hand, although PPR did not change consistently during D 1 receptor agonists, a significant and consistent decrease in IPSCs amplitude was seen, suggesting a mixture of postsynaptic (Flores-Hernández et al, 2000) and presynaptic (Centonze et al, 2003;Gao et al, 2003) D 1 effects. This latter effect is the opposite of that found on IPSCs from axon collaterals and striatonigral terminals (Radnikow and Misgeld, 1998), demonstrating that the same modulator may have opposite actions on different GABAergic connections and neurons.…”

Dopaminergic modulation of short-term synaptic plasticity at striatal inhibitory synapses

“…Variance-mean analysis (Fig. 5G) suggested that this action was postsynaptic (53). However, it coursed with a decrease in quantal amplitude (54), implying, perhaps, a mixture of pre-and postsynaptic actions.…”

GABAAReceptor Phospho-Dependent Modulation Is Regulated by Phospholipase C-Related Inactive Protein Type 1, a Novel Protein Phosphatase 1 Anchoring Protein

“…For these studies, we focused on dopamine D 1 receptors, which have been established previously to modify GABA A receptor function via a PKA-dependent mechanism (Hernandez et al, 2000). First, we examined the effects of D 1 receptor activation on GABA A receptor ␤3 subunit phosphorylation in wild-type and PRIP-1 Ϫ/Ϫ mice.…”