Inhibition by ATP of Hippocampal Synaptic Transmission Requires Localized Extracellular Catabolism by Ecto-Nucleotidases into Adenosine and Channeling to Adenosine A1Receptors

Abstract

ATP analogs substituted in the γ-phosphorus (ATPγS, β,γ-imido-ATP, and β,γ-methylene-ATP) were used to probe the involvement of P 2 receptors in the modulation of synaptic transmission in the hippocampus, because their extracellular catabolism was virtually not detected in CA1 slices. ATP and γ-substituted analogs were equipotent to inhibit synaptic transmission in CA1 pyramid synapses (IC 50 of 17–22 μ m). The inhibitory effect of ATP and γ-phosphorus-substituted ATP analogs (30 μ m) was not modified by the P 2 receptor antagonist suramin (100 μ m), was inhibited by 42–49% by the ecto-5′-nucleotidase inhibitor and α,β-methylene ADP (100 μ m), was inhibited by 74–85% by 2 U/ml adenosine deaminase (which converts adenosine into its inactive metabolite-inosine), and was nearly prevented by the adenosine A 1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10 n m). Stronger support for the involvement of extracellular adenosine formation as a main requirement for the inhibitory effect of ATP and γ-substituted ATP analogs was the observation that an inhibitor of adenosine uptake, dipyridamole (20 μ m), potentiated by 92–124% the inhibitory effect of ATP and γ-substituted ATP analogs (10 μ m), a potentiation similar to that obtained for 10 μ m adenosine (113%). Thus, the present results indicate that inhibition by extracellular ATP of hippocampal synaptic transmission requires localized extracellular catabolism by ecto-nucleotidases and channeling of the generated adenosine to adenosine A 1 receptors.