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The Journal of Neuroscience, March 15, 1998, 18(6):1987-1995

Inhibition by ATP of Hippocampal Synaptic Transmission Requires Localized Extracellular Catabolism by Ecto-Nucleotidases into Adenosine and Channeling to Adenosine A₁ Receptors

Rodrigo A. Cunha², Ana M. Sebastião¹, and J. A. Ribeiro¹

¹ Laboratory of Neurosciences, Faculty of Medicine, and ² Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, 1600 Lisbon, Portugal

ATP analogs substituted in the -phosphorus (ATPS, ,-imido-ATP, and ,-methylene-ATP) were used to probe the involvement of P₂ receptors in the modulation of synaptic transmission in the hippocampus, because their extracellular catabolism was virtually not detected in CA1 slices. ATP and -substituted analogs were equipotent to inhibit synaptic transmission in CA1 pyramid synapses (IC₅₀ of 17-22 µM). The inhibitory effect of ATP and -phosphorus-substituted ATP analogs (30 µM) was not modified by the P₂ receptor antagonist suramin (100 µM), was inhibited by 42-49% by the ecto-5'-nucleotidase inhibitor and ,-methylene ADP (100 µM), 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 A₁ receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10 nM). Stronger support for the involvement of extracellular adenosine formation as a main requirement for the inhibitory effect of ATP and -substituted ATP analogs was the observation that an inhibitor of adenosine uptake, dipyridamole (20 µM), potentiated by 92-124% the inhibitory effect of ATP and -substituted ATP analogs (10 µM), a potentiation similar to that obtained for 10 µM 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 A₁ receptors.

Key words: ATP; adenosine; ecto-nucleotidases; hippocampus; ATP analogs; P₂ receptors; A₁ receptors

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1861987-09$05.00/0

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