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Cited by 590Neuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase SignalingGenetics and Neurodevelopmental Disorders

A Synaptic Ras-GTPase Activating Protein (p135 SynGAP) Inhibited by CaM Kinase II

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Chen, Hong-Jung, Rojas-Soto, Michelle, Oguni, Asako, Kennedy, Mary B·1998·Neuron
DOI 10.1016/s0896-6273(00)80471-7
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Abstract

Ca2+ influx through N-methyl-D-aspartate- (NMDA-) type glutamate receptors plays a critical role in synaptic plasticity in the brain. One of the proteins activated by the increase in Ca2+ is CaM kinase II (CaMKII). Here, we report a novel synaptic Ras-GTPase activating protein (p135 SynGAP) that is a major component of the postsynaptic density, a complex of proteins associated with synaptic NMDA receptors. p135 SynGAP is almost exclusively localized at synapses in hippocampal neurons where it binds to and closely colocalizes with the scaffold protein PSD-95 and colocalizes with NMDA receptors. The Ras-GTPase activating activity of p135 SynGAP is inhibited by phosphorylation by CaMKII located in the PSD protein complex. Inhibition of p135 SynGAP by CaMKII will stop inactivation of GTP-bound Ras and thus could result in activation of the mitogen-activated protein (MAP) kinase pathway in hippocampal neurons upon activation of NMDA receptors.

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  • SynGAP1 is a Ras-GTPase activating protein located in the postsynaptic density of glutamatergic neurons and participates in dendritic spine maturation, glutamate receptor trafficking, and synaptic function.

    “Synaptic GTPase activating protein 1 (SynGAP1) is a Ras-GTPase activating protein localized in the PSD in glutamatergic neurons [66, 197] and involved in dendritic spine maturation, glutamate receptor trafficking and synaptic function [11].”

    From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [66]

  • SYNGAP1 encodes a synaptic RasGAP (SynGAP) largely localized to dendritic spines in neocortical pyramidal neurons, where it suppresses signaling linked to NMDAR-mediated plasticity and AMPAR membrane insertion.

    “SYNGAP1 encodes a synaptic RasGAP (SynGAP) that is largely localized to dendritic spines in neocortical pyramidal neurons (Chen et al., 1998; Kim et al., 1998; Zhang et al., 1999), where it suppresses signaling pathways linked to NMDA receptor (NMDAR) mediated synaptic plasticity and AMPA receptor (AMPAR) membrane insertion”

    From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Chen et al., 1998

  • The GABAergic elevation is likely explained by homeostatic upregulation caused by elevated network excitation triggered by prematurely developing spine synapses.

    “However, because SynGAP is selectively localized to excitatory synapses (Chen et al., 1998; Kim et al., 1998), this effect is likely explained by a homoeostatic upregulation of the GABAergic system caused by elevated network excitation triggered by prematurely developing spine synapses.”

    From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Chen et al., 1998

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Authors
Chen, H.-J., Rojas-Soto, M., Oguni, A., & Kennedy, M. B.
Affiliations
California Institute of Technology (US)
Corresponding author
Kennedy, Mary B
ORCID
Kennedy, Mary B
Venue
Neuron
Publisher
Elsevier BV
Published
1998-05
Volume
20
Issue
5
Pages
895-904
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/s0896-6273(00)80471-7
OpenAlex
W2087444241
Cited by
590
References
57
Citations by year
2026: 6 · 2025: 21 · 2024: 19 · 2023: 12 · 2022: 12 · 2021: 11 · 2020: 18 · 2019: 16 · 2018: 16 · 2017: 15 · 2016: 14 · 2015: 11 · 2014: 19 · 2013: 12 · 2012: 13
FWCI
18.06
Type
journal article
Language
en
Update notices
erratum (2002-01-03)
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R01NS028710, R01NS017660, NS-17660, NS28710)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Ras GTPase-activating protein, CaMKII, NMDA receptor, synaptic plasticity, postsynaptic density, PSD-95, Ras GTPase, MAPK signaling, hippocampal neurons, protein phosphorylation
MeSH terms
Animals, Brain, Carrier Proteins, Cells, Cultured, Enzyme Inhibitors, Hippocampus, Molecular Sequence Data, Neurons, Neuropeptides, Phosphorylation, RNA, Messenger, Substrate Specificity, Synapses, Receptors, N-Methyl-D-Aspartate, Sequence Homology, Amino Acid, Calcium-Calmodulin-Dependent Protein Kinases, ras Proteins, Glutamic Acid, GTP Phosphohydrolases, GTPase-Activating Proteins, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2

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