Adenosine A2A receptors inhibit the conductance of NMDA receptor channels in rat neostriatal neurons.
Whole-cell patch clamp experiments were carried out in rat striatal brain slices. In a subset of striatal neurons (70-80%), NMDA-induced inward currents were inhibited by the adenosine A2A receptor selective agonist CGS 21680. The non-selective adenosine receptor antagonist 8-(p-sulphophenyl)-theophylline and the A2A receptor selective antagonist 8-(3-chlorostyryl)caffeine abolished the inhibitory action of CGS 21680. Intracellular GDP-beta-S, which is known to prevent G protein-mediated reactions, also eliminated the effect of CGS 21680. Extracellular dibutyryl cAMP, a membrane permeable analogue of cAMP, and intracellular Sp-cAMPS, an activator of cAMP-dependent protein kinases (PKA), both abolished the CGS 21680-induced inhibition. By contrast, Rp-cAMPS and PKI 14-24 amide, two inhibitors of PKA had no effect. Intracellular U-73122 (a phospholipase C inhibitor) and heparin (an inositoltriphosphate antagonist) prevented the effect of CGS 21680. Finally, a more efficient buffering of intracellular Ca2+ by a substitution of EGTA (11 mM) by BAPTA (5.5 mM) acted like U-73122 or heparin. Hence, A2A receptors appear to negatively modulate NMDA receptor channel conductance via the phospholipase C/inositoltriphosphate/Ca2+ pathway rather than the adenylate cyclase/PKA pathway.
Nörenberg
W
W
Department of Pharmacology, University of Freiburg, Federal Republic of Germany.
Wirkner
K
K
Assmann
H
H
Richter
M
M
Illes
P
P
D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000037:antagonists & inhibitors; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D015398:Signal Transduction; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C081320:8-(3-chlorostyryl)caffeine; D002110:Caffeine; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D000241:Adenosine