The Journal of Neurophysiology Vol. 83 No. 1 January 2000, pp. 322-332
Copyright ©2000 by the American Physiological Society

Adenosine Receptor Expression and Modulation of Ca²⁺ Channels in Rat Striatal Cholinergic Interneurons

Department of Physiology and Institute for Neuroscience, Northwestern University Medical School, Chicago, Illinois 60611

Song, Wen-Jie, Tatiana Tkatch, and D. James Surmeier. Adenosine Receptor Expression and Modulation of Ca²⁺ Channels in Rat Striatal Cholinergic Interneurons. J. Neurophysiol. 83: 322-332, 2000. Adenosine is a potent regulator of acetylcholine release in the striatum, yet the mechanisms mediating this regulation are largely undefined. To begin to fill this gap, adenosine receptor expression and coupling to voltage-dependent Ca²⁺ channels were studied in cholinergic interneurons by combined whole cell voltage-clamp recording and single-cell reverse transcription-polymerase chain reaction. Cholinergic interneurons were identified by the presence of choline acetyltransferase mRNA. Nearly all of these interneurons (90%, n = 28) expressed detectable levels of A₁ adenosine receptor mRNA. A_2a and A_2b receptor mRNAs were less frequently detected. A₃ receptor mRNA was undetectable. Adenosine rapidly and reversibly reduced N-type Ca²⁺ currents in cholinergic interneurons. The A₁ receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine completely blocked the effect of adenosine. The IC₅₀ of the A₁ receptor selective agonist 2-chloro-N6-cyclopentyladenosine was 45 nM, whereas it was near 30 µM for the A_2a receptor agonist CGS-21680. Dialysis with GDPS or brief exposure to the G protein (G_i/o) alkylating agent N-ethylmaleimide also blocked the adenosine modulation. The reduction in N-type currents was partially reversed by depolarizing prepulses. A membrane-delimited pathway mediated the modulation, because it was not seen in cell-attached patches when agonist was applied to the bath. Activation of protein kinase C attenuated the adenosine modulation. Taken together, our results argue that activation of A₁ adenosine receptors in cholinergic interneurons reduces N-type Ca²⁺ currents via a membrane-delimited, G_i/o class G-protein pathway that is regulated by protein kinase C. These observations establish a cellular mechanism by which adenosine may serve to reduce acetylcholine release.