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Volume 17, Number 20, Issue of October 15, 1997 pp. 7673-7682
Copyright ©1997 Society for Neuroscience

Adenine Nucleotides Undergo Rapid, Quantitative Conversion to Adenosine in the Extracellular Space in Rat Hippocampus

Received June 5, 1997; revised August 4, 1997; accepted August 5, 1997.

Thomas V. Dunwiddie1, 2, Lihong Diao1, and William R. Proctor1, 2

1 Program in Neuroscience and Department of Pharmacology, University of Colorado Health Science Center, Denver, Colorado 80262, and 2 Veterans Administration Medical Research Service, Denver, Colorado 80220

There are multiple mechanisms by which adenine nucleotides can be released into the extracellular space in brain. Adenine nucleotides are converted extracellularly to adenosine, which then acts on adenosine receptors to elicit physiological responses, but the rate at which this conversion takes place is unknown. In the present experiments, adenine nucleotides were applied to individual hippocampal neurons, and the subsequent activation of a postsynaptic K+ conductance by adenosine A1 receptors was used to determine the rate of adenosine formation. None of the adenine nucleotides tested (cAMP, AMP, ADP, and ATP) activated A1 receptors directly at the concentrations tested (<= 200 µM). AMP, ADP, and ATP were all rapidly converted to adenosine, with a T1/2 for ATP conversion to adenosine of ~200 msec, and the last step in this pathway (transformation of AMP to adenosine by 5'-nucleotidase) seems to be the rate-limiting step. As we have reported previously, cAMP is converted to adenosine as well, but on a much slower time scale than any of the other nucleotides tested. These experiments demonstrate that fast, localized release of AMP, ADP, or ATP can result in a transient activation of adenosine receptors but that this is unlikely to occur with cAMP. The existence of a highly active ecto-nucleotidase pathway in brain provides a mechanism for the rapid generation of adenosine after the release of adenine nucleotides into the extracellular space.

Key words: adenosine; adenine nucleotides; adenosine receptors; hippocampus; electrophysiology; 5'-nucleotidase; P1 receptors




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