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Reaction mechanism determines NMDA receptor response to repetitive stimulation

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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Figure 1: Single-channel NR activity at 5 µM glutamate.
Figure 2: NR activity at several glutamate concentrations.
Figure 3: Simulated NR macroscopic responses to a single glutamate pulse.
Figure 4: NR response to repetitive stimulation (1-ms pulses of 1 mM glutamate).

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References

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

    Article  CAS  Google Scholar 

  2. Mainen, Z. F., Malinow, R. & Svoboda, K. Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated. Nature 399, 151–155 (1999)

    Article  ADS  CAS  Google Scholar 

  3. Anson, L. C., Chen, P. E., Wyllie, D. J., Colquhoun, D. & Schoepfer, R. 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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Diamond, J. S. & Jahr, C. E. Transporters buffer synaptically released glutamate on a submillisecond time scale. J. Neurosci. 17, 4672–4687 (1997)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Franks, K. M., Bartol, T. M. Jr & Sejnowski, T. J. A Monte Carlo model reveals independent signaling at central glutamatergic synapses. Biophys. J. 83, 2333–2348 (2002)

    Article  ADS  CAS  Google Scholar 

  8. Min, M. Y., Rusakov, D. A. & Kullmann, D. M. Activation of AMPA, kainate, and metabotropic receptors at hippocampal mossy fiber synapses: role of glutamate diffusion. Neuron 21, 561–570 (1998)

    Article  CAS  Google Scholar 

  9. McAllister, A. K. & Stevens, C. F. Nonsaturation of AMPA and NMDA receptors at hippocampal synapses. Proc. Natl Acad. Sci. USA 97, 6173–6178 (2000)

    Article  ADS  CAS  Google Scholar 

  10. Ishikawa, T., Sahara, Y. & Takahashi, T. A single packet of transmitter does not saturate postsynaptic glutamate receptors. Neuron 34, 613–621 (2002)

    Article  CAS  Google Scholar 

  11. Oertner, T. G., Sabatini, B. L., Nimchinsky, E. A. & Svoboda, K. Facilitation at single synapses probed with optical quantal analysis. Nature Neurosci. 5, 657–664 (2002)

    Article  CAS  Google Scholar 

  12. Nowak, L., Bregestovski, P., Ascher, P., Herbet, A. & Prochiantz, A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465 (1984)

    Article  ADS  CAS  Google Scholar 

  13. Traynelis, S. F. & Cull-Candy, S. G. Proton inhibition of N-methyl-d-aspartate receptors in cerebellar neurons. Nature 345, 347–350 (1990)

    Article  ADS  CAS  Google Scholar 

  14. Westbrook, G. L. & Mayer, M. L. Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons. Nature 328, 640–643 (1987)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Anson, L. C., Schoepfer, R., Colquhoun, D. & Wyllie, D. J. 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)

    Article  CAS  Google Scholar 

  19. Colquhoun, D. 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)

    Article  CAS  Google Scholar 

  20. Chen, N., Ren, J., Raymond, L. A. & Murphy, T. H. 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)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Cull-Candy, S., Brickley, S. & Farrant, M. NMDA receptor subunits: diversity, development and disease. Curr. Opin. Neurobiol. 11, 327–335 (2001)

    Article  CAS  Google Scholar 

  24. Yang, S. N., Tang, Y. G. & Zucker, R. S. Selective induction of LTP and LTD by postsynaptic [Ca2+]i elevation. J. Neurophysiol. 81, 781–787 (1999)

    Article  CAS  Google Scholar 

  25. Robert, A., Irizarry, S. N., Hughes, T. E. & Howe, J. R. Subunit interactions and AMPA receptor desensitization. J. Neurosci. 21, 5574–5586 (2001)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  27. Qin, F., Auerbach, A. & Sachs, F. Maximum likelihood estimation of aggregated Markov processes. Proc. R. Soc. Lond. B 264, 375–383 (1997)

    Article  ADS  CAS  Google Scholar 

  28. Magleby, K. L. & Pallotta, B. S. Burst kinetics of single calcium-activated potassium channels in cultured rat muscle. J. Physiol. (Lond.) 344, 605–623 (1983)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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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.

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Correspondence to Gabriela Popescu.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure S1

This figure illustrates the kinetic schemes used to fit single channel data obtained from NR1/2A receptors. (PPT 42 kb)

Supplementary Table S1

This document contains a table summarizing time constants for closed and open components in single channel currents NR1/2A receptors. (DOC 32 kb)

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. (DOC 44 kb)

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Popescu, G., Robert, A., Howe, J. et al. Reaction mechanism determines NMDA receptor response to repetitive stimulation. Nature 430, 790–793 (2004). https://doi.org/10.1038/nature02775

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