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Binding sites for permeant ions in the channel of NMDA receptors and their effects on channel block

Nature Neuroscience volume 1, pages 451–461 (1998)Cite this article

Abstract

We report the presence of binding sites for permeant monovalent cations at the internal and external entrances to the channel of NMDA receptors. We measured the effects of changing internal cesium (Cs+) and external sodium (Na+) concentrations on the channel-blocking kinetics of the adamantane derivatives IEM-1754 and IEM-1857. Binding of Na+, or of Cs+ after it permeates the channel, to sites at the external channel entrance prevents blockers from entering the channel. Binding of Na+ to a blocked channel prevents blocker unbinding. Cs+ binding to a site at the internal channel entrance prevents IEM-1754 from occupying the deeper of its two sites of block. The results show the critical effects of permeant ions on the kinetics, affinity and voltage-dependence of channel blockers.

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Figure 1: NMDA-activated single-channel current amplitudes recorded in each combination of solutions.
Figure 2: Measurement of effect of permeant cations on k+,app of the IEM drugs.
Figure 3: Voltage dependence of effects of permeant cations on k+,app of the IEM drugs.
Figure 4: Dependence on Na+o of τb and k-,app of IEM-1857.
Figure 5: Effect of Cs+i on τb of IEM-1754 at negative voltages.
Figure 6: Effects of permeant cations on the k-,app of IEM-1754.
Figure 7: Schematics of the channel of NMDA receptors during block by the IEM drugs.

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Acknowledgements

This work was supported by NIH Grants MH45817, MH00944 and MH45156. We thank Jacques Neyton, Philippe Ascher, Tom Blanpied, Jim Dilmore and Yingying Li-Smerin for comments on the manuscript, Jim Dilmore for help with figures and Juliann Jaumotte for technical assistance.

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Author notes

  1. Sergei M. Antonov

    Present address: Laboratoire de Neurobiologie, Ecole Normale Supérieure, 46 rue d'Ulm, 75005, Paris, France

Authors and Affiliations

  1. Department of Neuroscience, University of Pittsburgh, 15260, PA, USA

    Sergei M. Antonov & Jon W. Johnson

  2. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Science, St. Petersburg, 194223, Russia

    Sergei M. Antonov

  3. Institute of Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg, 197022, Russia

    Valeriy E. Gmiro

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Correspondence to Jon W. Johnson.

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Antonov, S., Gmiro, V. & Johnson, J. Binding sites for permeant ions in the channel of NMDA receptors and their effects on channel block. Nat Neurosci 1, 451–461 (1998). https://doi.org/10.1038/2167

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