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The Journal of Neuroscience, June 15, 2003, 23(12):4996-5003

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ATP Inhibits NMDA Receptors after Heterologous Expression and in Cultured Hippocampal Neurons and Attenuates NMDA-Mediated Neurotoxicity

Stefanie Ortinau,^1 * Bodo Laube,^2 * and Herbert Zimmermann¹

¹Biozentrum der J. W. Goethe-Universität, Arbeitskreis Neurochemie, Zoologisches Institut, D-60439 Frankfurt am Main, Germany, and ²Max-Planck-Institut für Hirnforschung, D-60439 Frankfurt am Main, Germany

We investigated the potential of ATP to inhibit heterologously expressed NMDA receptor subunit combinations, NMDA-induced currents in cultured hippocampal cells, and NMDA-induced neurotoxicity. The effect of ATP on diheteromeric NR1a/NR2A-D NMDA receptor (NR) combinations expressed in Xenopus laevis oocytes was studied by voltage-clamp recording. ATP strongly inhibited NMDA-induced inward currents only at the NR1a/NR2B receptor combination. At NMDA concentrations corresponding to the EC₅₀ value (20 µM), ATP revealed an IC₅₀ value of 135 µM. Mutation studies suggest that ATP exerts its inhibition via the glutamate-binding pocket of the NR2B subunit. Inosine 5'-triphosphate (ITP), GTP, and AMP also inhibited the recombinant NR1a/NR2B receptor, whereas UTP and CTP, ADP, or adenosine had no or only a small effect. Correspondingly, ATP inhibited NMDA-induced but not kainate-induced currents at cultured hippocampal neurons. An abundant expression of the NR2B subunit in the cultured neurons was verified by immunocytochemistry and blockade of NMDA-induced currents by the NR2B-selective antagonist ifenprodil. In addition we studied the role of ATP in NMDA-mediated neurotoxicity using cultured rat hippocampal cells. ATP exhibited a dose-dependent rescue effect when coapplied with the excitotoxicant NMDA, in contrast to ADP, AMP, and adenosine. The effect of ATP was mimicked by GTP and ITP but not by UTP and CTP. ATP had no effect on kainate-elicited neurotoxicity. Our results suggest that ATP can act as an inhibitor of NMDA receptors depending on receptor subunit composition and that it can attenuate NMDA-mediated neurotoxicity that is mediated neither by ATP nor by adenosine receptors.

Key words: adenosine; ATP; glutamate; GTP; hippocampus; kainate; neurotoxicity; NMDA receptor; P2 receptor

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Received Feb. 20, 2003; revised Mar. 24, 2003; accepted May. 24, 2003.

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