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Reaction mechanism determines NMDA receptor response to repetitive stimulation

Nature volume 430, pages 790793 (12 August 2004) | Download Citation

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Abstract

At central excitatory synapses, N-methyl-d-aspartate (NMDA) receptors, which have a high affinity for glutamate1, produce a slowly rising synaptic current in response to a single transmitter pulse and an additional current after a second, closely timed stimulus2. Here we show, by examining the kinetics of transmitter binding and channel gating in single-channel currents from recombinant NR1/NR2A receptors, that the synaptic response to trains of impulses is determined by the molecular reaction mechanism of the receptor. The rate constants estimated for the activation reaction predict that, after binding neurotransmitter, receptors hesitate for 4 ms in a closed high-affinity conformation before they either proceed towards opening or release neurotransmitter, with about equal probabilities. Because only about half of the initially fully occupied receptors become active, repetitive stimulation elicits currents with distinct waveforms depending on pulse frequency. This high-affinity/low-efficiency activation mechanism might serve as a link between stimulation frequency and the directionality of the ensuing synaptic plasticity.

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References

  1. 1.

    & Structure–activity relationships for amino acid transmitter candidates acting at N-methyl-d-aspartate and quisqualate receptors. J. Neurosci. 10, 2385–2399 (1990)

  2. 2.

    , & Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated. Nature 399, 151–155 (1999)

  3. 3.

    , , , & Identification of amino acid residues of the NR2A subunit that control glutamate potency in recombinant NR1/NR2A NMDA receptors. J. Neurosci. 18, 581–589 (1998)

  4. 4.

    Transmitter timecourse in the synaptic cleft: its role in central synaptic function. Trends Neurosci. 19, 163–171 (1996)

  5. 5.

    & Transporters buffer synaptically released glutamate on a submillisecond time scale. J. Neurosci. 17, 4672–4687 (1997)

  6. 6.

    & Saturation of postsynaptic receptors at central synapses? Curr. Opin. Neurobiol. 6, 395–403 (1996)

  7. 7.

    , & A Monte Carlo model reveals independent signaling at central glutamatergic synapses. Biophys. J. 83, 2333–2348 (2002)

  8. 8.

    , & Activation of AMPA, kainate, and metabotropic receptors at hippocampal mossy fiber synapses: role of glutamate diffusion. Neuron 21, 561–570 (1998)

  9. 9.

    & Nonsaturation of AMPA and NMDA receptors at hippocampal synapses. Proc. Natl Acad. Sci. USA 97, 6173–6178 (2000)

  10. 10.

    , & A single packet of transmitter does not saturate postsynaptic glutamate receptors. Neuron 34, 613–621 (2002)

  11. 11.

    , , & Facilitation at single synapses probed with optical quantal analysis. Nature Neurosci. 5, 657–664 (2002)

  12. 12.

    , , , & Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465 (1984)

  13. 13.

    & Proton inhibition of N-methyl-d-aspartate receptors in cerebellar neurons. Nature 345, 347–350 (1990)

  14. 14.

    & Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature 328, 640–643 (1987)

  15. 15.

    & Modal gating of NMDA receptors and the shape of their synaptic response. Nature Neurosci. 6, 476–483 (2003)

  16. 16.

    Modal gating of NMDA receptors. Trends Neurosci. 27, 231–233 (2004)

  17. 17.

    & The NMDA receptor gating machine: lessons from single channels. Neuroscientist 10, 192–198 (2004)

  18. 18.

    , , & Single-channel analysis of an NMDA receptor possessing a mutation in the region of the glutamate binding site. J. Physiol. (Lond.) 527, 225–237 (2000)

  19. 19.

    Binding, gating, affinity and efficacy: the interpretation of structure–activity relationships for agonists and of the effects of mutating receptors. Br. J. Pharmacol. 125, 924–947 (1998)

  20. 20.

    , , & Changes in agonist concentration dependence that are a function of duration of exposure suggest N-methyl-d-aspartate receptor nonsaturation during synaptic stimulation. Mol. Pharmacol. 59, 212–219 (2001)

  21. 21.

    & Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Science 258, 1007–1011 (1992)

  22. 22.

    et al. Functional and pharmacological differences between recombinant N-methyl-d-aspartate receptors. J. Neurophysiol. 79, 555–566 (1998)

  23. 23.

    , & NMDA receptor subunits: diversity, development and disease. Curr. Opin. Neurobiol. 11, 327–335 (2001)

  24. 24.

    , & Selective induction of LTP and LTD by postsynaptic [Ca2+]i elevation. J. Neurophysiol. 81, 781–787 (1999)

  25. 25.

    , , & Subunit interactions and AMPA receptor desensitization. J. Neurosci. 21, 5574–5586 (2001)

  26. 26.

    Restoration of single-channel currents using the segmental k-means method based on hidden Markov modeling. Biophys. J. 86, 1488–1501 (2004)

  27. 27.

    , & Maximum likelihood estimation of aggregated Markov processes. Proc. R. Soc. Lond. B 264, 375–383 (1997)

  28. 28.

    & Burst kinetics of single calcium-activated potassium channels in cultured rat muscle. J. Physiol. (Lond.) 344, 605–623 (1983)

  29. 29.

    , & A direct optimization approach to hidden Markov modeling for single channel kinetics. Biophys. J. 79, 1915–1927 (2000)

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Acknowledgements

We thank T. Bailey, M. Teeling and C. Nicolai for technical assistance. This work was supported by NIH grants to G.P. and A.A.

Author information

Affiliations

  1. University at Buffalo, Department of Physiology and Biophysics and Center for Single Molecule Biophysics, Buffalo, New York 14214, USA

    • Gabriela Popescu
    •  & Anthony Auerbach
  2. Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

    • Antoine Robert
    •  & James R. Howe

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Competing interests

The authors declare that they have no competing financial interests.

Corresponding author

Correspondence to Gabriela Popescu.

Supplementary information

Powerpoint files

  1. 1.

    Supplementary Figure S1

    This figure illustrates the kinetic schemes used to fit single channel data obtained from NR1/2A receptors.

Word documents

  1. 1.

    Supplementary Table S1

    This document contains a table summarizing time constants for closed and open components in single channel currents NR1/2A receptors.

  2. 2.

    Supplementary Table S2

    This file contains a table summarizing rate constants for L-mode gating NR1/2A receptors optimized with each of the kinetic schemes illustrated in Supplementary Figure S1.

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DOI

https://doi.org/10.1038/nature02775

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