Proteomic analysis of NMDA receptor–adhesion protein signaling complexes
Open accessAbstract
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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Glutamate receptors form multiprotein complexes with scaffold and signalling proteins including MAGUKs embedded in the PSD.
“Glutamate receptors form multiprotein complexes with large sets of scaffold and signalling proteins including MAGUKs43 that are embedded in the PSD.”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [43]
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Bramham, C. R. (2007) · Progress in Brain Research · doi:10.1016/s0079-6123(07)63025-8 · Cited by 69 · see citing works
Synapse diversity and synaptome architecture in human genetic disorders
Grant, S. G. N. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz178 · Cited by 67 · see citing works
“This revealed that 77 proteins assembled into large multiprotein complexes, and this increased the number of known proteins by 10-fold (1,2).”
BackgroundInfluentialSelf-citationSynapse proteomics of multiprotein complexes: en route from genes to nervous system diseases
Grant, S. G. N., Marshall, M. C., Page, K.-L., Cumiskey, M. A., & Armstrong, J. D. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi330 · Cited by 64 · see citing works
Self-citationA role for ERKII in synaptic pattern selectivity on the time‐scale of minutes
Ajay, S. M., & Bhalla, U. S. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03725.x · Cited by 64 · see citing works
Systems biology in neuroscience: bridging genes to cognition
Grant, S. G. (2003) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2003.09.016 · Cited by 53 · see citing works
Self-citationLiu, Z.-H., Ding, J.-J., Yang, Q.-Q., Song, H.-Z., Chen, X.-T., Xu, Y., Xiao, G.-R., & Wang, H.-L. (2016) · Scientific Reports · doi:10.1038/srep32492 · Cited by 53 · see citing works
Ferreira, J. S., Schmidt, J., Rio, P., Águas, R., Rooyakkers, A., Li, K. W., Smit, A. B., Craig, A. M., & Carvalho, A. L. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.3567-14.2015 · Cited by 50 · see citing works
Warnet, X. L., Bakke Krog, H., Sevillano‐Quispe, O. G., Poulsen, H., & Kjaergaard, M. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.14842 · Cited by 50 · see citing works
Sassoé‐Pognetto, M., Utvik, J. K., Camoletto, P., Watanabe, M., Stephenson, F. A., Bredt, D. S., & Ottersen, O. P. (2003) · Journal of Comparative Neurology · doi:10.1002/cne.10745 · Cited by 45 · see citing works
Garside, M. L., Turner, P. R., Austen, B., Strehler, E. E., Beesley, P. W., & Empson, R. M. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.04.059 · Cited by 41 · see citing works
Reciprocal regulation of microRNA and mRNA profiles in neuronal development and synapse formation
Manakov, S. A., Grant, S. G., & Enright, A. J. (2009) · BMC Genomics · doi:10.1186/1471-2164-10-419 · Cited by 34 · see citing works
Self-citationPredicting post-synaptic activity in proteins with data mining
Pappa, G. L., Baines, A. J., & Freitas, A. A. (2005) · Bioinformatics · doi:10.1093/bioinformatics/bti1102 · Cited by 20 · see citing works
The postsynaptic density in excitatory synapses is composed of clustered, heterogeneous nanoblocks
Sun, R., Allen, J. P., Mao, Z., Wilson, L., Haider, M., Alten, B., Zhou, Z., Wang, X., & Zhou, Q. (2025) · Journal of Cell Biology · doi:10.1083/jcb.202406133 · Cited by 20 · see citing works
Molecular organization and assembly of the postsynaptic density of excitatory brain synapses.
Kim, E., & Ko, J. (2006) · Results and Problems in Cell Differentiation · doi:10.1007/400_011 · Cited by 11 · see citing works
- 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
- green
- hdl.handle.net
- 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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