NMDA Receptor Subunit Composition Controls Synaptic Plasticity by Regulating Binding to CaMKII
Open accessAbstract
Calcium entry through postsynaptic NMDA-Rs and subsequent activation of CaMKII trigger synaptic plasticity in many brain regions. Active CaMKII can bind to NMDA-Rs, but the physiological role of this interaction is not well understood. Here, we test if association between active CaMKII and synaptic NMDA-Rs is required for synaptic plasticity. Switching synaptic NR2B-containing NMDA-Rs that bind CaMKII with high affinity with those containing NR2A, a subunit with low affinity for CaMKII, dramatically reduces LTP. Expression of NR2A with mutations that increase association to active CaMKII recovers LTP. Finally, driving into synapses NR2B with mutations that reduce association to active CaMKII prevents LTP. Spontaneous activity-driven potentiation shows similar results. We conclude that association between active CaMKII and NR2B is required for different forms of synaptic enhancement. The switch from NR2B to NR2A content in synaptic NMDA-Rs normally observed in many brain regions may contribute to reduced plasticity by controlling the binding of active CaMKII.
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Ca2+/CaM peeling away the autoinhibitory segment results in the phosphorylation of T286 and also the binding of CaMKII to GluN2B even without prior autophosphorylation, both of which maintain CaMKII in an active state.
“The first step involves Ca2+/CaM peeling away the autoinhibitory segment from the kinase domain. This results in the phosphorylation of T286 and also the binding of CaMKII to GluN2B even without prior autophosphorylation, both of which maintain CaMKII in an active state (64, 78, 119–121, 221).”
From Synaptic memory and CaMKII (2023) · cites this paper as [119]
The Introduction (page not provided) says Ca2+/CaM exposes CaMKII’s catalytic site and that binding to NR2B then keeps CaMKII active independently of its phosphorylation state. It mentions Thr286 autophosphorylation as a requirement for a proposed second NR2B binding site, but does not say that Ca2+/CaM exposure results in Thr286 phosphorylation or that this phosphorylation maintains activity. (LLM, conf=0.83)
Experimental — accuracy not yet measuredBinding of CaMKII to GluN2B is critical for the synaptic enhancement caused by CaMKII.
“This binding of CaMKII to GluN2B is critical for the synaptic enhancement caused by CaMKII (see sect. 6) (119–122).”
From Synaptic memory and CaMKII (2023) · cites this paper as [119]
The NR2A/NR2B ratio is an important determinant of NMDA receptor signaling.
“Given that the NR2A/NR2B ratio appears to be an important determinant of NMDA receptor signaling”
From Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132 (2010) · cites this paper as Barria and Malinow, 2005
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- Authors
- Barria, A., & Malinow, R.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- ORCID
- Malinow, Roberto
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2005-10
- Volume
- 48
- Issue
- 2
- Pages
- 289-301
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2146521940
- Cited by
- 709
- References
- 7
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 19 · 2023: 23 · 2022: 32 · 2021: 28 · 2020: 21 · 2019: 31 · 2018: 37 · 2017: 32 · 2016: 34 · 2015: 37 · 2014: 45 · 2013: 44 · 2012: 49
- FWCI
- 15.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- NMDA receptor subunit composition, CaMKII, synaptic plasticity, long-term potentiation, NR2B, NR2A, calcium influx, postsynaptic receptors
- MeSH terms
- Benzenesulfonamides, Animals, Animals, Newborn, Benzylamines, Cell Line, Electric Stimulation, Cricetinae, Hippocampus, Magnesium, Membrane Potentials, Neuronal Plasticity, Neurons, Piperidines, Protein Binding, Sulfonamides, Synapses, Time Factors, Transfection, Gene Expression, Receptors, N-Methyl-D-Aspartate, Mutagenesis, Rats, Sprague-Dawley, Calcium-Calmodulin-Dependent Protein Kinases, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Protein Kinase Inhibitors, Green Fluorescent Proteins, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2, In Vitro Techniques
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