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Cited by 22Neuroscience and Neuropharmacology ResearchReceptor Mechanisms and SignalingNicotinic Acetylcholine Receptors Study

CaMKII-mediated phosphorylation of GluN2B regulates recombinant NMDA receptor currents in a chloride-dependent manner

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Tavalin, Steven J., Colbran, Roger J.·2017·Molecular and Cellular Neuroscience
DOI 10.1016/j.mcn.2016.12.002PMC PMC5315591
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Abstract

Some forms of long-term synaptic plasticity require docking of Ca 2+/calmodulin-dependent protein kinase II α (CaMKIIα) to residues 1290-1309 within the intracellular C-terminal tail of the N-methyl-d-aspartate (NMDA) receptor GluN2B subunit. The phosphorylation of Ser1303 within this region destabilizes CaMKII binding. Interestingly, Ser1303 is a substrate for CaMKII itself, as well as PKC and DAPK1, but these kinases have been reported to have contradictory effects on the activity of GluN2B-containing NMDA receptors. Here, we re-assessed the effect of CaMKII on NMDA receptor desensitization in heterologous cells, as measured by the ratio of steady-state to peak currents induced during 3s agonist applications. CaMKIIα co-expression or infusion of constitutively active CaMKII limits the extent of desensitization and preserves current amplitude with repeated stimulation of recombinant GluN1A/GluN2B when examined using low intracellular chloride (Cl-) levels, characteristic of neurons beyond the first postnatal week. In contrast, CaMKIIα enhances the acute rate and extent of desensitization when intracellular Cl- concentrations are high. The apparent dependence of CaMKIIα effects on NMDA receptor desensitization on Cl- concentrations is consistent with the presence of a Ca 2+-activated Cl- conductance endogenous to HEK 293 cells, which was confirmed by photolysis of caged-Ca 2+. However, Ca 2+-activated Cl- conductances are unaffected by CaMKIIα expression, indicating that CaMKII affects agonist-induced whole cell currents via modulation of the NMDA receptor. In support of this idea, CaMKIIα modulation of GluN2B-NMDA receptors is abrogated by the phospho-null mutation of Ser1303 in GluN2B to alanine and occluded by phospho-mimetic mutation of Ser1303 to aspartate regardless of intracellular Cl- concentration. Thus, CaMKII-mediated phosphorylation of GluN2B-containing NMDA receptors reduces desensitization at physiological (low) intracellular Cl-, perhaps serving as a feed-forward mechanism to sustain NMDA-mediated Ca 2+ entry and continued CaMKII activation during learning and memory.

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  • Phosphorylation of S1303 reduces desensitization of GluN2B-containing receptors.

    “and reduces desensitization of GluN2B-containing receptors (129).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [129]

    The Discussion says Ser1303 phosphorylation is sufficient to reduce desensitization when intracellular chloride is low. The claim omits that condition: the Results report that a phospho-mimetic S1303D mutation instead increased apparent desensitization when chloride was the major intracellular anion. (LLM, conf=0.90)

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Cited by

Sorted by citations

Authors
Tavalin, S. J., & Colbran, R. J.
Affiliations
  • University of Tennessee Health Science Center (US)
  • Vanderbilt University (US)
Corresponding author
Tavalin, Steven J.
ORCID
Venue
Molecular and Cellular Neuroscience
Publisher
Elsevier BV
Published
2017-03
Volume
79
Pages
45-52
ISSN
1044-7431 (ISSN-L)
DOI
10.1016/j.mcn.2016.12.002
PMC
PMC5315591
OpenAlex
W2563412042
Cited by
22
References
3
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 3 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 4
FWCI
1.88
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Molecular and Cellular Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIMH (R01MH063232)
  • NINDS (R01NS76637)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Keywords
CaMKII, GluN2B, NMDA receptor, receptor desensitization, intracellular chloride, synaptic plasticity, long-term potentiation, CaMKIIα
MeSH terms
Action Potentials, Chlorides, Humans, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Receptors, N-Methyl-D-Aspartate, Calcium Signaling, Calcium-Calmodulin-Dependent Protein Kinase Type 2, HEK293 Cells

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