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

René A. W. Frank; Noboru H. Komiyama; Tomás J. Ryan; Fei Zhu; Thomas J O'Dell; Seth G. N. Grant

doi:10.1038/ncomms11264

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

René A. W. Frank, Noboru H. Komiyama, Tomás J. Ryan, Fei Zhu, Thomas J O'Dell, Seth G. N. Grant

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Abstract / Description of output

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.

Original language	English
Article number	11264
Number of pages	13
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11264
Publication status	Published - 27 Apr 2016

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Grant S NMDA receptors
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Seth Grant
- seth.granted.acuk
- Deanery of Clinical Sciences - Personal Chair of Molecular Neuroscience
- Centre for Clinical Brain Sciences
- Edinburgh Neuroscience
Person: Academic: Research Active
Noboru Komiyama
- Deanery of Clinical Sciences - Senior Lecturer
- Centre for Clinical Brain Sciences
- Edinburgh Neuroscience
Person: Academic: Research Active

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title = "NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation",

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.",

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AU - Frank, René A. W.

AU - Komiyama, Noboru H.

AU - Ryan, Tomás J.

AU - Zhu, Fei

AU - O'Dell, Thomas J

AU - Grant, Seth G. N.

PY - 2016/4/27

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AB - 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.

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

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Seth Grant

Noboru Komiyama

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