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On the regulation of NMDA receptors by nitric oxide

Authors

  • Rachel Hopper,

    1. Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6BT, United Kingdom
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  • Barrie Lancaster,

    1. Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6BT, United Kingdom
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  • John Garthwaite

    1. Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6BT, United Kingdom
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: Professor John Garthwaite, as above.
E-mail: john.garthwaite@ucl.ac.uk

Abstract

Nitric oxide (NO) is generated in central synapses on activation of N-methyl-d-aspartate (NMDA) receptors and exerts physiological effects by changing cGMP levels. NO has frequently also been claimed to engage a different mechanism, namely the covalent modification of thiol residues (S-nitrosation), and thereby exert a negative feedback on NMDA receptors. Tests of this hypothesis were conducted by recording NMDA receptor-mediated synaptic potentials in the CA1 area of rat hippocampal slices. Manipulations designed to increase or decrease endogenous NO levels had no effect. Addition of exogenous NO using a NONOate donor in concentrations up to 30-fold higher than those needed to evoke maximal cGMP accumulation also had no effect. Nevertheless, in agreement with previous findings, photolysis of a caged NO derivative with UV light led to an enduring block of synaptic NMDA receptors. To address these contradictory results, NMDA receptor-mediated currents were recorded from HEK-293 cells transfected with NR1 and NR2A subunits. As found in slices, photolysis of caged NO inhibited the currents whereas perfusion of NO (up to 5 µm) was ineffective. However, when NO was supplied at a concentration found to be effective when released photolytically (5 µm) and the cells simultaneously exposed to the UV light used for photolysis, NMDA receptor-mediated currents were inhibited. This effect was not observed at more physiological NO concentrations (10 nm range). The results indicate that neither endogenous NO nor exogenous NO in supra-physiological concentration inhibits synaptic NMDA receptors; the combination of high NO concentration and UV light can give an artifactual result.

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