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NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation

Author

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  • René A. W. Frank

    (Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK
    MRC Laboratory of Molecular Biology)

  • Noboru H. Komiyama

    (Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK)

  • Tomás J. Ryan

    (RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Massachusetts Institute of Technology
    Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Howard Hughes Medical Institute, Massachusetts Institute of Technology)

  • Fei Zhu

    (Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK)

  • Thomas J. O’Dell

    (David Geffen School of Medicine and UCLA Integrative Center for Learning and Memory, University of California Los Angeles)

  • Seth G. N. Grant

    (Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK)

Abstract

How neuronal proteomes self-organize is poorly understood because of their inherent molecular and cellular complexity. Here, focusing on mammalian synapses we use blue-native PAGE and ‘gene-tagging’ of GluN1 to report the first biochemical purification of endogenous NMDA receptors (NMDARs) directly from adult mouse brain. We show that NMDARs partition between two discrete populations of receptor complexes and ∼1.5 MDa supercomplexes. We tested the assembly mechanism with six mouse mutants, which indicates a tripartite requirement of GluN2B, PSD93 and PSD95 gate the incorporation of receptors into ∼1.5 MDa supercomplexes, independent of either canonical PDZ-ligands or GluN2A. Supporting the essential role of GluN2B, quantitative gene-tagging revealed a fourfold molar excess of GluN2B over GluN2A in adult forebrain. NMDAR supercomplexes are assembled late in postnatal development and triggered by synapse maturation involving epigenetic and activity-dependent mechanisms. Finally, screening the quaternary organization of 60 native proteins identified numerous discrete supercomplexes that populate the mammalian synapse.

Suggested Citation

  • René A. W. Frank & Noboru H. Komiyama & Tomás J. Ryan & Fei Zhu & Thomas J. O’Dell & Seth G. N. Grant, 2016. "NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11264
    DOI: 10.1038/ncomms11264
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