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Gain control of NMDA-receptor currents by intracellular sodium

Nature volume 396, pages 469–474 (1998)Cite this article

Abstract

The influx of Na+ is fundamental to electrical signalling in the nervous system and is essential for such basic signals as action potentials and excitatory postsynaptic potentials1. During periods of bursting or high levels of discharge activity, large increases in intracellular Na+ concentration ([Na+]i) are produced in neuronal soma and dendrites2,3,4. However, the intracellular signalling function of raised postsynaptic [Na+]i is unknown. Here we show that [Na+]i regulates the function of NMDA (N-methyl-D-aspartate) receptors, a principal subtype of glutamate receptor5. NMDA-receptor-mediated whole-cell currents and NMDA-receptor single-channel activity were increased by raising [Na+]i and channel activity decreased upon lowering [Na+]i; therefore, the activity of NMDA channels tracks changes in [Na+]i. We found that the sensitivity of the channel to Na+ was set by a Src kinase that is associated with the channel. Raising [Na+]i selectively increased synaptic responses mediated by NMDA receptors, but not by non-NMDA receptors. Thus, the change in postsynaptic [Na+]i that occurs during neuronal activity is a signal for controlling the gain of excitatory synaptic transmission. This mechanism may be important for NMDA-receptor-dependent plasticity and toxicity in the central nervous system.

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Figure 1: NMDA-channel activity is regulated by intracellular Na+.
Figure 2: NMDA single-channel activity is potentiated by Na+ influx through remote NMDA receptors.
Figure 3: NMDA single-channel activity is upregulated by activating non-NMDA receptors and voltage-gated Na+ channels.
Figure 4: Synaptic NMDA receptors but not non-NMDA receptors are regulated by intracellularly applied Na+.
Figure 5: Raising the Na+ concentration on the cytoplasmic face of excised patches increases NMDA-channel activity during activation.

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Acknowledgements

We thank J. F. MacDonald, Y. T. Wang, L. Y. Wang and Y. De Koninck for comments on the manuscript; Y. De Koninck for software used in analysis; and J. L. Hicks for preparing and maintaining cell cultures and for technical assistance. This work was supported by a grant from the Medical Research Council of Canada to M.W.S. and by the Nicole Fealdman Memorial Fund. M.W.S. is an MRC Scientist and X.-M.Y is an MRC Scholar.

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Authors and Affiliations

  1. Programme in Brain and Behaviour, Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Xian-Min Yu & Michael W. Salter

  2. Departments of Physiology, University of Toronto, Toronto, Ontario, M5G 1G6, Ontario, Canada

    Xian-Min Yu & Michael W. Salter

  3. Oral Physiology, University of Toronto, Toronto, M5G 1G6, Ontario, Canada

    Xian-Min Yu

  4. Molecular Neurobiology Section, Clarke Institute of Psychiatry, M5T 1R8, Toronto, Ontario, Canada

    Xian-Min Yu

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Correspondence to Michael W. Salter.

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Yu, XM., Salter, M. Gain control of NMDA-receptor currents by intracellular sodium. Nature 396, 469–474 (1998). https://doi.org/10.1038/24877

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