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Structure and different conformational states of native AMPA receptor complexes


Ionotropic glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system1,2. Their modulation is believed to affect learning and memory, and their dysfunction has been implicated in the pathogenesis of neurological and psychiatric diseases1,2. Despite a wealth of functional data, little is known about the intact, three-dimensional structure of these ligand-gated ion channels. Here, we present the structure of native AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; AMPA-Rs) purified from rat brain, as determined by single-particle electron microscopy. Unlike the homotetrameric recombinant GluR2 (ref. 3), the native heterotetrameric AMPA-R adopted various conformations, which reflect primarily a variable separation of the two dimeric extracellular amino-terminal domains. Members of the stargazin/TARP family of transmembrane proteins co-purified with AMPA-Rs and contributed to the density representing the transmembrane region of the complex. Glutamate and cyclothiazide markedly altered the conformational equilibrium of the channel complex, suggesting that desensitization is related to separation of the N-terminal domains. These data provide a glimpse of the conformational changes of an important ligand-gated ion channel of the brain.

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Figure 1: Negative staining and Fab decoration of AMPA-Rs.
Figure 2: Three-dimensional reconstruction of AMPA-Rs and placement of crystal structures into the density map.
Figure 3: TARP contributes to the density of the transmembrane domain.
Figure 4: Ligand-dependent conformational change of AMPA receptors.


  1. Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002)

    CAS  Article  Google Scholar 

  2. Wollmuth, L. P. & Sobolevsky, A. I. Structure and gating of the glutamate receptor ion channel. Trends Neurosci. 27, 321–328 (2004)

    CAS  Article  Google Scholar 

  3. Tichelaar, W., Safferling, M., Keinanen, K., Stark, H. & Madden, D. R. The Three-dimensional structure of an ionotropic glutamate receptor reveals a dimer-of-dimers assembly. J. Mol. Biol. 344, 435–442 (2004)

    CAS  Article  Google Scholar 

  4. Keinanen, K. et al. A family of AMPA-selective glutamate receptors. Science 249, 556–560 (1990)

    ADS  CAS  Article  Google Scholar 

  5. Hollmann, M., O'Shea-Greenfield, A., Rogers, S. W. & Heinemann, S. Cloning by functional expression of a member of the glutamate receptor family. Nature 342, 643–648 (1989)

    ADS  CAS  Article  Google Scholar 

  6. Safferling, M. et al. First images of a glutamate receptor ion channel: oligomeric state and molecular dimensions of GluRB homomers. Biochemistry 40, 13948–13953 (2001)

    CAS  Article  Google Scholar 

  7. Rosenmund, C., Stern-Bach, Y. & Stevens, C. F. The tetrameric structure of a glutamate receptor channel. Science 280, 1596–1599 (1998)

    ADS  CAS  Article  Google Scholar 

  8. Chen, G. Q., Cui, C., Mayer, M. L. & Gouaux, E. Functional characterization of a potassium-selective prokaryotic glutamate receptor. Nature 402, 817–821 (1999)

    ADS  CAS  Article  Google Scholar 

  9. Wenthold, R. J., Petralia, R. S., Blahos, J. II & Niedzielski, A. S. Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons. J. Neurosci. 16, 1982–1989 (1996)

    CAS  Article  Google Scholar 

  10. Armstrong, N. & Gouaux, E. Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core. Neuron 28, 165–181 (2000)

    CAS  Article  Google Scholar 

  11. Sobolevsky, A. I., Yelshansky, M. V. & Wollmuth, L. P. The outer pore of the glutamate receptor channel has 2-fold rotational symmetry. Neuron 41, 367–378 (2004)

    CAS  Article  Google Scholar 

  12. Horning, M. S. & Mayer, M. L. Regulation of AMPA receptor gating by ligand binding core dimers. Neuron 41, 379–388 (2004)

    CAS  Article  Google Scholar 

  13. Stern-Bach, Y. et al. Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins. Neuron 13, 1345–1357 (1994)

    CAS  Article  Google Scholar 

  14. Hollmann, M., Maron, C. & Heinemann, S. N-glycosylation site tagging suggests a three transmembrane domain topology for the glutamate receptor GluR1. Neuron 13, 1331–1343 (1994)

    CAS  Article  Google Scholar 

  15. Bennett, J. A. & Dingledine, R. Topology profile for a glutamate receptor: three transmembrane domains and a channel-lining reentrant membrane loop. Neuron 14, 373–384 (1995)

    CAS  Article  Google Scholar 

  16. Ohi, M., Li, Y., Cheng, Y. & Walz, T. Negative staining and image classification—powerful tools in modern electron microscopy. Biol. Proc. Online 6, 23–34 (2004)

    CAS  Article  Google Scholar 

  17. Frank, J. Three-dimensional Electron Microscopy of Macromolecular Assemblies (Academic, San Diego, 1996)

    Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  19. Armstrong, N., Sun, Y., Chen, G. Q. & Gouaux, E. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395, 913–917 (1998)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  22. Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000)

    ADS  CAS  Article  Google Scholar 

  23. Tomita, S., Fukata, M., Nicoll, R. A. & Bredt, D. S. Dynamic interaction of stargazin-like TARPs with cycling AMPA receptors at synapses. Science 303, 1508–1511 (2004)

    ADS  CAS  Article  Google Scholar 

  24. Patneau, D. K., Vyklicky, L. Jr & Mayer, M. L. Hippocampal neurons exhibit cyclothiazide-sensitive rapidly desensitizing responses to kainate. J. Neurosci. 13, 3496–3509 (1993)

    CAS  Article  Google Scholar 

  25. Sommer, B. et al. Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science 249, 1580–1585 (1990)

    ADS  CAS  Article  Google Scholar 

  26. Swanson, G. T., Kamboj, S. K. & Cull-Candy, S. G. Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. J. Neurosci. 17, 58–69 (1997)

    CAS  Article  Google Scholar 

  27. Goodsell, D. S. & Olson, A. J. Structural symmetry and protein function. Annu. Rev. Biophys. Biomol. Struct. 29, 105–153 (2000)

    CAS  Article  Google Scholar 

  28. Pasternack, A. et al. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels lacking the N-terminal domain. J. Biol. Chem. 277, 49662–49667 (2002)

    CAS  Article  Google Scholar 

  29. Ayalon, G. & Stern-Bach, Y. Functional assembly of AMPA and kainate receptors is mediated by several discrete protein-protein interactions. Neuron 31, 103–113 (2001)

    CAS  Article  Google Scholar 

  30. Passafaro, M., Nakagawa, T., Sala, C. & Sheng, M. Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2. Nature 424, 677–681 (2003)

    ADS  CAS  Article  Google Scholar 

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This work was supported by an NIH grant (to T.W.). M.S. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Morgan Sheng or Thomas Walz.

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Supplementary information

Supplementary Data

This file contains Supplementary Methods and legends for Supplementary Figures 1-5 and Table 1. (DOC 47 kb)

Supplementary Figure 1

Purification of AMPA-Rs. (JPG 99 kb)

Supplementary Figure 2

Plot of the angle distributions and comparison of reprojections from 3D models with the corresponding raw particle images. (JPG 150 kb)

Supplementary Figure 3

3D density map of AMPA-R in the type I conformation filtered to 42 Å (FSC = 0.5 criterion) or 31 Å (FSC = 0.142 criterion). (JPG 87 kb)

Supplementary Figure 4

ClustalW alignment of mGluR1 (extracellular domain), LIVBP, and GluR2-NTD. (JPG 163 kb)

Supplementary Figure 5

Class averages of particles obtained under different drug treatments. (JPG 378 kb)

Supplementary Table 1

Peptides and corresponding proteins identified by LC/MS/MS tandem mass spectrometry analysis of the bands indicated by asterisks in Fig. 3a. (XLS 15 kb)

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Nakagawa, T., Cheng, Y., Ramm, E. et al. Structure and different conformational states of native AMPA receptor complexes. Nature 433, 545–549 (2005).

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