Modulation of hippocampal glutamatergic transmission by ATP is dependent on adenosine a(1) receptors.
Excitatory glutamatergic synapses in the hippocampal CA1 region of rats are potently inhibited by purines, including adenosine, ATP, and ATP analogs. Adenosine A(1) receptors are known to mediate at least part of the response to adenine nucleotides, either because adenine nucleotides activate A(1) receptors directly, or activate them secondarily upon the nucleotides' conversion to adenosine. In the present studies, the inhibitory effects of adenosine, ATP, the purportedly stable ATP analog adenosine-5'-O-(3-thio)triphosphate (ATPgammaS), and cyclic AMP were examined in mice with a null mutation in the adenosine A(1) receptor gene. ATPgammaS displaced the binding of A(1)-selective ligands to intact brain sections and brain homogenates from adenosine A(1) receptor wild-type animals. In homogenates, but not in intact brain sections, this displacement was abolished by adenosine deaminase. In hippocampal slices from wild-type mice, purines abolished synaptic responses, but slices from mice lacking functional A(1) receptors showed no synaptic modulation by adenosine, ATP, cAMP, or ATPgammaS. In slices from heterozygous mice the dose-response curve for both adenosine and ATP was shifted to the right. In all cases, inhibition of synaptic responses by purines could be blocked by prior treatment with the competitive adenosine A(1) receptor antagonist 8-cyclopentyltheophylline. Taken together, these results show that even supposedly stable adenine nucleotides are rapidly converted to adenosine at sites close to the A(1) receptor, and that inhibition of synaptic transmission by purine nucleotides is mediated exclusively by A(1) receptors.
Masino
Susan A
SA
Department of Pharmacology and Program in Neuroscience, University of Colorado Health Sciences Center, Denver 80262, USA. susan.masino@uchsc.edu
Diao
Lihong
L
Illes
Peter
P
Zahniser
Nancy R
NR
Larson
Gaynor A
GA
Johansson
Björn
B
Fredholm
Bertil B
BB
Dunwiddie
Thomas V
TV
D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D018047:Receptors, Purinergic P1 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014970:Xanthines / Q000494:pharmacology
D018047:Receptors, Purinergic P1; D014970:Xanthines; C022571:adenosine 5'-O-(3-thiotriphosphate); D018698:Glutamic Acid; D000255:Adenosine Triphosphate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine