The Journal of Neurophysiology Vol. 77 No. 2 February 1997, pp. 1003-1015
Copyright ©1997 The American Physiological Society

D₂ Dopamine Receptors Reduce N-Type Ca²⁺ Currents in Rat Neostriatal Cholinergic Interneurons Through a Membrane-Delimited, Protein-Kinase-C-Insensitive Pathway

Zhen Yan, Wen-Jie Song, and D. James Surmeier

Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee, Memphis, Tennessee 38163

Yan, Zhen, Wen-Jie Song, and D. James Surmeier. D₂ dopamine receptors reduce N-type Ca²⁺ currents in rat neostriatal cholinergic interneurons through a membrane-delimited, protein-kinase-C-insensitive pathway. J. Neurophysiol. 77: 1003-1015, 1997. Dopamine has long been known to regulate the activity of striatal cholinergic interneurons and the release of acetylcholine. Yet, the cellular mechanisms by which this regulation occurs have not been elucidated. One way in which dopamine might act is by modulating voltage-dependent Ca²⁺ channels. To test this hypothesis, the impact of dopaminergic agonists on Ca²⁺ channels in neostriatal cholinergic interneurons was studied by combined whole cell voltage-clamp recording and single-cell reverse transcription-polymerase chain reactions. Cholinergic interneurons were identified by the presence of choline acetyltransferase mRNA. Nearly all interneurons tested (90%, n = 17) coexpressed D₂ (short and long isoforms) and D_1b (D₅) dopamine receptor mRNAs. D_1a receptor mRNA was found in only a small subset (20%) of the sample and D₃ and D₄ receptor mRNAs were undetectable. D₂ receptor agonists rapidly and reversibly reduced N-type Ca²⁺ currents. D_1b/D_1a receptor activation had little or no effect on Ca²⁺ currents. The D₂ receptor antagonist sulpiride blocked the effect of D₂ agonists. Dialysis with guanosine-5-O-(2-thiodiphosphate) or brief exposure to the G protein (G_i/o) alkylating agent N-ethylmaleimide also blocked the D₂ modulation. The reduction in N-type currents was neither accompanied by kinetic slowing nor significantly reversed by depolarizing prepulses. The D₂ receptor effects were mediated by a membrane-delimited pathway, because the modulation was not seen in cell-attached patches when agonist was applied to the bath and was not disrupted by perturbations in cytosolic signaling pathways known to be linked to D₂ receptors. Activation of M2 muscarinic receptors occluded the D₂ modulation, suggesting a shared signaling element. However, activation of protein kinase C attenuated the M2 modulation without significantly affecting the D₂ modulation. Taken together, our results suggest that activation of D₂ dopamine receptors in cholinergic interneurons reduces N-type Ca²⁺ currents via a membrane-delimited, G_i/o class G protein pathway that is not regulated by protein kinase C. This signaling pathway may underlie the ability of D₂ receptors to reduce striatal acetylcholine release.

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