D2Dopamine Receptors Reduce N-Type Ca2+Currents in Rat Neostriatal Cholinergic Interneurons Through a Membrane-Delimited, Protein-Kinase-C-Insensitive Pathway

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Abstract
Yan, Zhen, Wen-Jie Song, and D. James Surmeier. D2dopamine 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 D1b(D5) dopamine receptor mRNAs. D1areceptor mRNA was found in only a small subset (20%) of the sample and D3and D4receptor mRNAs were undetectable. D2receptor agonists rapidly and reversibly reduced N-type Ca2+currents. D1b/D1areceptor activation had little or no effect on Ca2+currents. The D2receptor antagonist sulpiride blocked the effect of D2agonists. Dialysis with guanosine-5′-O-(2-thiodiphosphate) or brief exposure to the G protein (Gi/o) alkylating agent N-ethylmaleimide also blocked the D2modulation. The reduction in N-type currents was neither accompanied by kinetic slowing nor significantly reversed by depolarizing prepulses. The D2receptor 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 D2receptors. Activation of M2 muscarinic receptors occluded the D2modulation, suggesting a shared signaling element. However, activation of protein kinase C attenuated the M2 modulation without significantly affecting the D2modulation. Taken together, our results suggest that activation of D2dopamine receptors in cholinergic interneurons reduces N-type Ca2+currents via a membrane-delimited, Gi/oclass G protein pathway that is not regulated by protein kinase C. This signaling pathway may underlie the ability of D2receptors to reduce striatal acetylcholine release.