Article | Published:

The structure–energy landscape of NMDA receptor gating

Nature Chemical Biology volume 13, pages 12321238 (2017) | Download Citation

Abstract

N-Methyl-D-aspartate (NMDA) receptors are the main calcium-permeable excitatory receptors in the mammalian central nervous system. The NMDA receptor gating is complex, exhibiting multiple closed, open, and desensitized states; however, central questions regarding the conformations and energetics of the transmembrane domains as they relate to the gating states are still unanswered. Here, using single-molecule Förster resonance energy transfer (smFRET), we map the energy landscape of the first transmembrane segment of the Rattus norvegicus NMDA receptor under resting and various liganded conditions. These results show kinetically and structurally distinct changes associated with apo, agonist-bound, and inhibited receptors linked by a linear mechanism of gating at this site. Furthermore, the smFRET data suggest that allosteric inhibition by zinc occurs by an uncoupling of the agonist-induced changes at the extracellular domains from the gating motions leading to an apo-like state, while dizocilpine, a pore blocker, stabilizes multiple closely packed transmembrane states.

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Acknowledgements

Methods and additional data can be found in the supplementary materials. This project was supported by NIH grant R35GM122528 to V.J., K99NS094761to D.M.M., American Heart Association Fellowship 16POST30030007 to S.A.S., Schissler Foundation Fellowship to D.M.D., and Welch Foundation Grant C-1787 to C.F.L.

Author information

Author notes

    • David M MacLean

    Present address: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA.

Affiliations

  1. Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Drew M Dolino
    • , David M MacLean
    • , Sana A Shaikh
    •  & Vasanthi Jayaraman
  2. Biochemistry and Molecular Biology Graduate Program, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Drew M Dolino
    •  & Vasanthi Jayaraman
  3. Department of Chemistry, Rice University, Houston, Texas, USA.

    • Sudeshna Chatterjee
    • , Charlotte Flatebo
    • , Logan D C Bishop
    •  & Christy F Landes
  4. Department of Electrical and Computer Engineering, Rice University, Houston, Texas, USA.

    • Christy F Landes

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Contributions

D.M.D. performed the mutations and prepared the labeled proteins, analyzed the smFRET data, and contributed to designing the research, interpreting the results, and writing the manuscript. S.C. performed the smFRET measurements, analyzed the smFRET data, and contributed to designing the research, interpreting the results, and writing the manuscript. D.M.M. and S.A.S. performed the electrophysiology. C.F. and L.D.C.B. analyzed the smFRET data. C.F.L., and V.J. analyzed the smFRET data and contributed to designing the research, interpreting the results, and writing the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Christy F Landes or Vasanthi Jayaraman.

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    Supplementary Results, Supplementary Figures 1–7

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DOI

https://doi.org/10.1038/nchembio.2487