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The Journal of Neuroscience, August 11, 2004, 24(32):7128-7139; doi:10.1523/JNEUROSCI.2093-04.2004

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Cellular/Molecular
Ecto-Nucleotidases and Nucleoside Transporters Mediate Activation of Adenosine Receptors on Hippocampal Mossy Fibers by P2X₇ Receptor Agonist 2'-3'-O-(4-Benzoylbenzoyl)-ATP

Maria Kukley,¹ Pia Stausberg,¹ Giselind Adelmann,² Iain P. Chessell,³ and Dirk Dietrich¹

¹Department of Neurosurgery, University Clinic Bonn, D-53105 Bonn, Germany, ²Department of Anatomy and Cell Biology, University Freiburg, D-79104 Freiburg, Germany, and ³Pain Research, GlaxoSmithKline, Harlow CM19 5AD, United Kingdom

The ionotropic and cytolytic P2X₇ receptor is typically found on immune cells, where it is involved in the release of cytokines. Recently, P2X₇ receptors were reported to be localized to presynaptic nerve terminals and to modulate transmitter release. In the present study, we reassessed this unexpected role of P2X₇ receptors at hippocampal mossy fiber-CA3 synapses. In agreement with previous findings, the widely used P2X₇ agonist 2'-3'-O-(4-benzoylbenzoyl)-adenosine-5'-triphosphate (BzATP) clearly depressed field potentials (fEPSPs); however, no evidence for an involvement of P2X₇ receptors could be obtained. First, depression of fEPSPs by BzATP was unchanged in P2X₇^-/- mice. Second, experiments using P2X₇^-/- mice, immunohistochemistry, and electron microscopy showed that the antigen detected by frequently used P2X₇ antibodies is not compatible with a plasmalemmal P2X₇ receptor. Third, BzATP did not alter Ca²⁺ levels in synaptic terminals. In contrast, the depression of fEPSPs by BzATP was fully blocked by adenosine (A₁) receptor antagonists. Furthermore, the application of BzATP also activated postsynaptic A₁ receptor-coupled K⁺ channels. This effect of BzATP was mimicked by ATP and adenosine and was completely prevented by enzymes specifically degrading adenosine. Activation of A₁-coupled K⁺ channels by BzATP was dependent on ecto-nucleotidases, extracellular enzymes that convert ATP to adenosine. Moreover, the opening of A₁-coupled K⁺ channels by BzATP was dependent on nucleoside transporters. Taken together, our results indicate that BzATP is extracellularly catabolized to Bz-adenosine and subsequently hetero-exchanged for intracellular adenosine and then depresses mossy fiber fEPSPs through presynaptic A₁ receptors rather than through P2X₇ receptors. Thus, the present study casts doubts on the neuronal localization of P2X₇ receptors in rodent hippocampus.

Key words: SB 203580; presynaptic; Ca²⁺ imaging; ecto-nucleotidases; nucleoside transporter; transmitter release

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Received May 30, 2004; revised July 1, 2004; accepted July 4, 2004.

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