Cited by 1,194Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersReceptor Mechanisms and Signaling

Proteomic analysis of NMDA receptor–adhesion protein signaling complexes

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Husi, Holger, Ward, Malcolm A., Choudhary, Jyoti S., Blackstock, Walter P., Grant, Seth G. N.·2000·Nature Neuroscience

Abstract

N-methyl-d-aspartate receptors (NMDAR) mediate long-lasting changes in synapse strength via downstream signaling pathways. We report proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins organized into receptor, adaptor, signaling, cytoskeletal and novel proteins, of which 30 are implicated from binding studies and another 19 participate in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impairs learning and with 22 proteins alters synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition.

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Authors
Husi, H., Ward, M. A., Choudhary, J. S., Blackstock, W. P., & Grant, S. G. N.
Affiliations
University of Edinburgh (GB)
Corresponding author
Grant, Seth G. N.
Venue
Nature Neuroscience
Published
2000-07
Volume
3
Issue
7
Pages
661-669
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W1500368251
Cited by
1,194
References
53
Citations by year
2026: 10 · 2025: 10 · 2024: 31 · 2023: 19 · 2022: 20 · 2021: 22 · 2020: 24 · 2019: 25 · 2018: 36 · 2017: 35 · 2016: 36 · 2015: 30 · 2014: 38 · 2013: 22 · 2012: 44
FWCI
33.62
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • ERA (submittedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
Funders
Wellcome Trust
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
NMDA receptor, protein complexes, adhesion molecules, cadherins, L1CAM, metabotropic glutamate receptors, MAPK signaling, kinases and phosphatases, GTPase-activating protein, Ras, synaptic plasticity, learning disabilities, neurofibromatosis type 1, mouse brain
MeSH terms
Animals, Brain, Cytoskeletal Proteins, Humans, Nerve Tissue Proteins, Protein Kinases, Mass Spectrometry, Signal Transduction, Cadherins, Receptors, N-Methyl-D-Aspartate, Neurotransmitter Agents, Mice

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