Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking
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NMDA receptors (NMDARs) control bidirectional synaptic plasticity by regulating postsynaptic AMPA receptors (AMPARs). Here we show that NMDAR activation can have differential effects on AMPAR trafficking, depending on the subunit composition of NMDARs. In mature cultured neurons, NR2A-NMDARs promote, whereas NR2B-NMDARs inhibit, the surface expression of GluR1, primarily by regulating its surface insertion. In mature neurons, NR2B is coupled to inhibition rather than activation of the Ras-ERK pathway, which drives surface delivery of GluR1. Moreover, the synaptic Ras GTPase activating protein (GAP) SynGAP is selectively associated with NR2B-NMDARs in brain and is required for inhibition of NMDAR-dependent ERK activation. Preferential coupling of NR2B to SynGAP could explain the subtype-specific function of NR2B-NMDARs in inhibition of Ras-ERK, removal of synaptic AMPARs, and weakening of synaptic transmission.
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Disrupting SynGAP expression in dissociated hippocampal neurons can enhance or suppress dendritic spine function.
“In addition, disrupting SynGAP expression in dissociated hippocampal neurons can enhance dendritic spine function (Kim et al., 2005; Rumbaugh et al., 2006) or suppress it (Krapivinsky et al., 2004).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Kim et al., 2005
SynGAP shapes developmental synaptic function through its synaptic GAP activity, suppressing biochemical signaling cascades in dendritic spines that promote synapse growth and AMPA receptor insertion.
“Mechanistically, SynGAP shapes developmental synaptic function through its synaptic GAP activity, where it suppresses many biochemical signaling cascades within dendritic spines that promote growth of synapses and insertion of AMPARs (Kim et al., 2005; Krapivinsky et al., 2004; Rumbaugh et al., 2006).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Kim et al., 2005
The role of SynGAP in regulating dendritic spine synapse function has been controversial, with some studies reporting repression and others stimulation.
“However, the role that SynGAP plays in neurons to regulate dendritic spine synapse function has been controversial because some studies report that SynGAP is a repressor of these synapses (Kim et al., 2005; Rumbaugh et al., 2006; Vazquez et al., 2004), while others report that it stimulates them (Krapivinsky et al., 2004; McMahon et al., 2012).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Kim et al., 2005
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- Authors
- Kim, M. J., Dunah, A. W., Wang, Y. T., & Sheng, M.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of British Columbia Hospital (CA)
- Corresponding author
- Sheng, Morgan
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2005-06
- Volume
- 46
- Issue
- 5
- Pages
- 745-760
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2032596004
- Cited by
- 494
- References
- 49
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 12 · 2023: 13 · 2022: 8 · 2021: 10 · 2020: 11 · 2019: 23 · 2018: 25 · 2017: 29 · 2016: 21 · 2015: 21 · 2014: 24 · 2013: 18 · 2012: 32
- FWCI
- 13.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2968 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- 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, NR2A, NR2B, AMPA receptor trafficking, GluR1, Ras/ERK signaling, SynGAP, synaptic plasticity, synaptic transmission, receptor subunit composition
- MeSH terms
- Animals, Cell Membrane, Cells, Cultured, Hippocampus, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Receptors, AMPA, ras Proteins, MAP Kinase Signaling System, Protein Transport, Extracellular Signal-Regulated MAP Kinases, Rats
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