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Mechanism of differential control of NMDA receptor activity by NR2 subunits

Abstract

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are a major class of excitatory neurotransmitter receptors in the central nervous system. They form glutamate-gated ion channels that are highly permeable to calcium and mediate activity-dependent synaptic plasticity1. NMDAR dysfunction is implicated in multiple brain disorders, including stroke, chronic pain and schizophrenia2. NMDARs exist as multiple subtypes with distinct pharmacological and biophysical properties that are largely determined by the type of NR2 subunit (NR2A to NR2D) incorporated in the heteromeric NR1/NR2 complex1,3,4. A fundamental difference between NMDAR subtypes is their channel maximal open probability (Po), which spans a 50-fold range from about 0.5 for NR2A-containing receptors to about 0.01 for receptors containing NR2C and NR2D; NR2B-containing receptors have an intermediate value (about 0.1)5,6,7,8,9. These differences in Po confer unique charge transfer capacities and signalling properties on each receptor subtype4,6,10,11. The molecular basis for this profound difference in activity between NMDAR subtypes is unknown. Here we show that the subunit-specific gating of NMDARs is controlled by the region formed by the NR2 amino-terminal domain (NTD), an extracellular clamshell-like domain previously shown to bind allosteric inhibitors12,13,14,15, and the short linker connecting the NTD to the agonist-binding domain (ABD). The subtype specificity of NMDAR Po largely reflects differences in the spontaneous (ligand-independent) equilibrium between open-cleft and closed-cleft conformations of the NR2-NTD. This NTD-driven gating control also affects pharmacological properties by setting the sensitivity to the endogenous inhibitors zinc and protons. Our results provide a proof of concept for a drug-based bidirectional control of NMDAR activity by using molecules acting either as NR2-NTD ‘closers’ or ‘openers’ promoting receptor inhibition or potentiation, respectively.

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Figure 1: The NR2 NTD+L region controls NMDAR Po.
Figure 2: Locking open the NR2-NTD increases NMDAR activity.
Figure 3: The NR2 NTD+L region controls zinc and proton sensitivities of NMDARs.
Figure 4: Model for the control of NMDAR activity by the N-terminal domain of NR2.

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References

  1. Dingledine, R., Borges, K., Bowie, D. & Traynelis, S. F. The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61 (1999)

    CAS  PubMed  Google Scholar 

  2. Kemp, J. A. & McKernan, R. M. NMDA receptor pathways as drug targets. Nature Neurosci. 5 (Suppl.). 1039–1042 (2002)

    Article  CAS  Google Scholar 

  3. Paoletti, P. & Neyton, J. NMDA receptor subunits: function and pharmacology. Curr. Opin. Pharmacol. 7, 39–47 (2007)

    Article  CAS  Google Scholar 

  4. Cull-Candy, S. G. & Leszkiewicz, D. N. Role of distinct NMDA receptor subtypes at central synapses. Sci. STKE 2004, re16 (2004)

    PubMed  Google Scholar 

  5. Chen, N., Luo, T. & Raymond, L. A. Subtype-dependence of NMDA receptor channel open probability. J. Neurosci. 19, 6844–6854 (1999)

    Article  CAS  Google Scholar 

  6. Erreger, K., Dravid, S. M., Banke, T. G., Wyllie, D. J. & Traynelis, S. F. Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. J. Physiol. (Lond.) 563, 345–358 (2005)

    Article  CAS  Google Scholar 

  7. Wyllie, D. J., Behe, P. & Colquhoun, D. Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors. J. Physiol. (Lond.) 510, 1–18 (1998)

    Article  CAS  Google Scholar 

  8. Dravid, S. M., Prakash, A. & Traynelis, S. F. Activation of recombinant NR1/NR2C NMDA receptors. J. Physiol. (Lond.) 586, 4425–4439 (2008)

    Article  CAS  Google Scholar 

  9. Popescu, G., Robert, A., Howe, J. R. & Auerbach, A. Reaction mechanism determines NMDA receptor response to repetitive stimulation. Nature 430, 790–793 (2004)

    Article  ADS  CAS  Google Scholar 

  10. Liu, Y. et al. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo . J. Neurosci. 27, 2846–2857 (2007)

    Article  CAS  Google Scholar 

  11. Liu, L. et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304, 1021–1024 (2004)

    Article  ADS  CAS  Google Scholar 

  12. Paoletti, P. et al. Molecular organization of a zinc binding N-terminal modulatory domain in a NMDA receptor subunit. Neuron 28, 911–925 (2000)

    Article  CAS  Google Scholar 

  13. Low, C. M., Zheng, F., Lyuboslavsky, P. & Traynelis, S. F. Molecular determinants of coordinated proton and zinc inhibition of N-methyl-d-aspartate NR1/NR2A receptors. Proc. Natl Acad. Sci. USA 97, 11062–11067 (2000)

    Article  ADS  CAS  Google Scholar 

  14. Choi, Y. B. & Lipton, S. A. Identification and mechanism of action of two histidine residues underlying high-affinity Zn2+ inhibition of the NMDA receptor. Neuron 23, 171–180 (1999)

    Article  CAS  Google Scholar 

  15. Perin-Dureau, F., Rachline, J., Neyton, J. & Paoletti, P. Mapping the binding site of the neuroprotectant ifenprodil on NMDA receptors. J. Neurosci. 22, 5955–5965 (2002)

    Article  CAS  Google Scholar 

  16. Jones, K. S., VanDongen, H. M. & VanDongen, A. M. The NMDA receptor M3 segment is a conserved transduction element coupling ligand binding to channel opening. J. Neurosci. 22, 2044–2053 (2002)

    Article  CAS  Google Scholar 

  17. Yuan, H., Erreger, K., Dravid, S. M. & Traynelis, S. F. Conserved structural and functional control of N-methyl-d-aspartate receptor gating by transmembrane domain M3. J. Biol. Chem. 280, 29708–29716 (2005)

    Article  CAS  Google Scholar 

  18. Blanke, M. L. & VanDongen, A. M. Constitutive activation of the N-methyl-d-aspartate receptor via cleft-spanning disulfide bonds. J. Biol. Chem. 283, 21519–21529 (2008)

    Article  CAS  Google Scholar 

  19. Rachline, J., Perin-Dureau, F., Le Goff, A., Neyton, J. & Paoletti, P. The micromolar zinc-binding domain on the NMDA receptor subunit NR2B. J. Neurosci. 25, 308–317 (2005)

    Article  CAS  Google Scholar 

  20. Gielen, M. et al. Structural rearrangements of NR1/NR2A NMDA receptors during allosteric inhibition. Neuron 57, 80–93 (2008)

    Article  CAS  Google Scholar 

  21. Sun, Y. et al. Mechanism of glutamate receptor desensitization. Nature 417, 245–253 (2002)

    Article  ADS  CAS  Google Scholar 

  22. Mayer, M. L. Glutamate receptors at atomic resolution. Nature 440, 456–462 (2006)

    Article  ADS  CAS  Google Scholar 

  23. Tang, C., Schwieters, C. D. & Clore, G. M. Open-to-closed transition in apo maltose-binding protein observed by paramagnetic NMR. Nature 449, 1078–1082 (2007)

    Article  ADS  CAS  Google Scholar 

  24. Kniazeff, J. et al. Locking the dimeric GABAB G-protein-coupled receptor in its active state. J. Neurosci. 24, 370–377 (2004)

    Article  CAS  Google Scholar 

  25. Mony, L. et al. Structural basis of NR2B-selective antagonist recognition by N-methyl-d-aspartate receptors. Mol. Pharmacol. 75, 60–74 (2009)

    Article  CAS  Google Scholar 

  26. Zheng, F. et al. Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A. Nature Neurosci. 4, 894–901 (2001)

    Article  CAS  Google Scholar 

  27. Marvin, J. S. & Hellinga, H. W. Manipulation of ligand binding affinity by exploitation of conformational coupling. Nature Struct. Biol. 8, 795–798 (2001)

    Article  CAS  Google Scholar 

  28. Low, C. M. et al. Molecular determinants of proton-sensitive N-methyl-d-aspartate receptor gating. Mol. Pharmacol. 63, 1212–1222 (2003)

    Article  CAS  Google Scholar 

  29. Lisman, J. E. et al. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 31, 234–242 (2008)

    Article  CAS  Google Scholar 

  30. Furukawa, H., Singh, S. K., Mancusso, R. & Gouaux, E. Subunit arrangement and function in NMDA receptors. Nature 438, 185–192 (2005)

    Article  ADS  CAS  Google Scholar 

  31. Paoletti, P., Ascher, P. & Neyton, J. High-affinity zinc inhibition of NMDA NR1-NR2A receptors. J. Neurosci. 17, 5711–5725 (1997)

    Article  CAS  Google Scholar 

  32. Erreger, K. & Traynelis, S. F. Zinc inhibition of rat NR1/NR2A N-methyl-d-aspartate receptors. J. Physiol. (Lond.) 586, 763–778 (2008)

    Article  CAS  Google Scholar 

  33. Schorge, S., Elenes, S. & Colquhoun, D. Maximum likelihood fitting of single channel NMDA activity with a mechanism composed of independent dimers of subunits. J. Physiol. (Lond.) 569, 395–418 (2005)

    Article  CAS  Google Scholar 

  34. Colquhoun, D. & Sigworth, F. J. in Single-channel Recording (eds Sakmann, B. & Neher, E.) 483–587 (Plenum, 1995)

    Book  Google Scholar 

  35. Sigworth, F. J. & Sine, S. M. Data transformations for improved display and fitting of single-channel dwell time histograms. Biophys. J. 52, 1047–1054 (1987)

    Article  CAS  Google Scholar 

  36. Jackson, M. B., Wong, B. S., Morris, C. E., Lecar, H. & Christian, C. N. Successive openings of the same acetylcholine receptor channel are correlated in open time. Biophys. J. 42, 109–114 (1983)

    Article  CAS  Google Scholar 

  37. Kunishima, N. et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407, 971–977 (2000)

    Article  ADS  CAS  Google Scholar 

  38. Doyle, D. A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77 (1998)

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

We thank B. Barbour, P.-J. Corringer, J. Neyton and D. Stroebel for comments on the manuscript, and S. Carvalho, M. Casado and M. Gendrel for experimental help. This work was supported by the Ministère de la Recherche (M.G., L.M.), the Université Pierre et Marie Curie (UPMC) and the Fondation pour la Recherche Médicale (FRM) (M.G.), NIH grant R01 MH045817 (J.W.J.), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Agence Nationale pour la Recherche (ANR), GlaxoSmithKline and an Équipe FRM grant (P.P.).

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Correspondence to Pierre Paoletti.

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Gielen, M., Retchless, B., Mony, L. et al. Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature 459, 703–707 (2009). https://doi.org/10.1038/nature07993

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