DOI: 10.1152/jn.2000.83.5.2996. D<sub>1</sub>Dopamine Receptor Activation Reduces GABA<sub>A</sub>Receptor Currents in Neostriatal Neurons Through a PKA/DARPP-32/PP1 Signaling Cascade

D1Dopamine Receptor Activation Reduces GABAAReceptor Currents in Neostriatal Neurons Through a PKA/DARPP-32/PP1 Signaling Cascade

10.1152/jn.2000.83.5.2996

Crossref journal-article

American Physiological Society

Journal of Neurophysiology (24)

Abstract

Dopamine is a critical determinant of neostriatal function, but its impact on intrastriatal GABAergic signaling is poorly understood. The role of D1dopamine receptors in the regulation of postsynaptic GABAAreceptors 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 D1dopamine receptor agonist SKF 81297 reduced GABA-evoked currents in most medium spiny neurons. The D1dopamine receptor antagonist SCH 23390 blocked the effect of SKF 81297. Membrane-permeant cAMP analogues mimicked the effect of D1dopamine receptor stimulation, whereas an inhibitor of protein kinase A (PKA; Rp-8-chloroadenosine 3′,5′ cyclic monophosphothioate) attenuated the response to D1dopamine 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 β1 subunit of the GABAAreceptor—a known substrate of PKA—in medium spiny neurons. Immunoprecipitation assays of radiolabeled proteins revealed that D1dopamine receptor stimulation increased phosphorylation of GABAAreceptor β1/β3 subunits. The D1dopamine receptor-induced phosphorylation of β1/β3 subunits was attenuated significantly in neostriata from DARPP-32 mutants. Voltage-clamp recordings corroborated these results, revealing that the efficacy of the D1dopamine receptor modulation of GABAAcurrents was reduced in DARPP-32-deficient medium spiny neurons. These results argue that D1dopamine receptor stimulation in neostriatal medium spiny neurons reduces postsynaptic GABAAreceptor currents by activating a PKA/DARPP-32/protein phosphatase 1 signaling cascade targeting GABAAreceptor β1 subunits.

Bibliography

Flores-Hernandez, J., Hernandez, S., Snyder, G. L., Yan, Z., Fienberg, A. A., Moss, S. J., Greengard, P., & Surmeier, D. J. (2000). D1Dopamine Receptor Activation Reduces GABAAReceptor Currents in Neostriatal Neurons Through a PKA/DARPP-32/PP1 Signaling Cascade. Journal of Neurophysiology, 83(5), 2996â3004.

Authors 8

Jorge Flores-Hernandez (first)
Salvador Hernandez (additional)
Gretchen L. Snyder (additional)
Zhen Yan (additional)
Allen A. Fienberg (additional)
Stephen J. Moss (additional)
Paul Greengard (additional)
D. James Surmeier (additional)

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Dates

Type	When
Created	7 years, 8 months ago (Dec. 21, 2017, 8:44 a.m.)
Deposited	2 months ago (June 28, 2025, 11:37 p.m.)
Indexed	3 days, 13 hours ago (Aug. 30, 2025, 1:19 p.m.)
Issued	25 years, 4 months ago (May 1, 2000)
Published	25 years, 4 months ago (May 1, 2000)
Published Print	25 years, 4 months ago (May 1, 2000)

Funders 0

None

BibTeX

@article{Flores_Hernandez_2000, title={D1Dopamine Receptor Activation Reduces GABAAReceptor Currents in Neostriatal Neurons Through a PKA/DARPP-32/PP1 Signaling Cascade}, volume={83}, ISSN={1522-1598}, url={http://dx.doi.org/10.1152/jn.2000.83.5.2996}, DOI={10.1152/jn.2000.83.5.2996}, number={5}, journal={Journal of Neurophysiology}, publisher={American Physiological Society}, author={Flores-Hernandez, Jorge and Hernandez, Salvador and Snyder, Gretchen L. and Yan, Zhen and Fienberg, Allen A. and Moss, Stephen J. and Greengard, Paul and Surmeier, D. James}, year={2000}, month=may, pages={2996–3004} }

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